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Background: Autophagy is a lysosome-mediated catabolic process that maintains cell homeostasis and survival. It occurs not only in normal cells such as cardiac muscle cells, neurons, and pancreatic acinar cells but also in various benign and malignant tumors. The abnormal level of intracellular autophagy is closely related to multiple pathophysiological processes, including aging, neurodegeneration, infectious diseases, immune disorders, and cancer. Autophagy mainly plays a dual role in life and death by regulating cell survival, proliferation, and death, thus being involved in the occurrence, development, and treatment of cancer. It is also involved in chemotherapy resistance by a dual role, since it not only promotes the occurrence of drug resistance but also reverses it. Previous findings suggest that the regulation of autophagy can be used as an effective strategy in tumor therapy. Summary: Recent studies found that small molecules from natural products and their derivatives exert anticancer activity by regulating the level of autophagy in tumor cells. Key Messages: Therefore, this review article describes the mechanism of autophagy, the role of autophagy in normal cells and tumor cells, and the research progress on the anticancer molecular mechanism of targets regulating cell autophagy. The aim is to provide a theoretical basis for developing autophagy inhibitors or activators to improve anticancer efficacy.
© 2023 S. Karger AG, Basel
IntroductionIn recent years, the overall incidence and mortality of cancer have increased, and cancer has become one of the leading causes of death [1-3]. Currently, surgical interventions, chemotherapy, and radiotherapy are the main comprehensive treatments to cure cancer [4-6]. However, their therapeutic effect is not satisfactory due to the toxicity of radiotherapy and chemotherapy and the occurrence of drug resistance [7, 8]. Therefore, it is necessary to find new targeted anticancer drugs with high efficiency and low toxicity. Autophagy plays an essential role in the occurrence, development, drug resistance, and treatment of cancer [9]. Autophagy is a self-degradation mechanism in widespread cells, also known as type II cell death, which degrades misfolded proteins and damaged or aging organelles through the lysosomes. It plays a vital role in cell proliferation, apoptosis, migration, and invasion of tumors [10, 11]. Autophagy is usually maintained at a low level under normal conditions. Still, it is activated when cells are in a state of stress [12] to help them deal with adverse stimuli. Many researchers have explored drugs targeting autophagy regulation based on understanding autophagy and the relationship between autophagy and tumors.
Autophagy plays contradictory regulatory roles in tumor cells. When the tumor is not yet developed, autophagy inhibits tumor proliferation by removing abnormal proteins and maintaining the integrity of the cell genome. However, once the cancer is formed, autophagy provides nutrients for tumor cells such as nucleotides, amino acids, and fatty acids by recycling them and ensuring tumor cells’ survival and growth [13, 14]. Nevertheless, long-term and excessive autophagy can lead to autophagic cell death [15, 16]. Autophagy participates in the occurrence and development of tumors and drug resistance, making it involved in the effect of cancer treatment [9, 17, 18]. The impact of the clinical treatment against cancer can be significantly improved by regulating the level of autophagy in tumor cells to cause autophagic or autophagy-related death in different tumor types and different stages of the tumor [19]. This review summarizes the research progress of targeted regulation of autophagy for anticancer therapy to provide some guidance for exploring efficient autophagy inhibitors or activators.
Molecular Mechanism of AutophagyAutophagy is a continuous process involving various genes, proteins, and multiple signaling pathways [18]. It consists of several sequential steps such as initiation, nucleation, extension, maturation, fusion, and degradation [20, 21].
Initiation and Nucleation of AutophagyWhen nutrition is adequate, rapamycin complex 1 (mTORC1), which is a nutritional regulatory factor, induces the phosphorylation of the autophagy-associated protein13 (ATG13) and blocks the interaction of ATG13 with Unc51-like kinase 1 (ULK1) and with the 200 kDa family-interacting protein (FIP200). It inactivates the ULK complex (composed of the ULK family kinase, ATG13, and FIP200) in cells to inhibit autophagy. However, when cells are under intracellular and extracellular stress stimulations such as hypoxia or nutritional deprivation, mTORC1 is hampered and then ULK1 dephosphorylates and dissociates from mTORC1. As a result, phosphorylation is deactivated at specific sites of ULK1 (Ser637 and Ser758) and ATG13 (Ser258). ATG13 then anchors ULK1 to the preautophagosome structure (PAS) [22-26], a membrane structure mainly located on the endoplasmic reticulum. PAS is involved in the assembly, elongation, and completion of the autophagic vesicle membranes in the cytoplasm [27]. ULK1 locates ATG13 on PAS and regulates the interaction between FIP200 and ULK1. When ATG13 and ULK1 bind to PAS, almost all the autophagy-associated proteins (ATG proteins) are recruited and bind to PAS, participating in the assembly and formation of the autophagic vesicles [28, 29].
When the energy level in cells decreases, the AMP-activated protein kinase (AMPK) is activated, which activates ULK1 by the downregulation of the phosphorylation of mTORC1 or directly by the phosphorylation of ULK1 [30]. The activated ULK complex during the nucleation of autophagy activates the PI3K (class III phosphatidylinositol 3-kinase) complex, which includes Beclin-1, VPS34 (PI3K), VPS15, ATG14L, and autophagy protein 1-activated molecules (AMBRA-1) regulated by Beclin1. The activated PI3K complex promotes autophagy nucleation by inducing the formation of local PI3P (phosphatidylinositol-3-phosphate) in the autophagy vesicles. PI3P on PAS recruits effector proteins such as WIPIs (WD-repeat protein Interacting with PhosphoInositides) and DFCP1 (double-FYVE-containing protein 1), which provide for the extension of the autophagic vesicles [31, 32]. The membrane structures from various organelles such as the Golgi matrix, endoplasmic reticulum, and lysosomes form cup-shaped structures at PAS and participate in the formation of the autophagic vesicles [20, 33].
Formation of Autophagy VesiclesWhen WIPIs bind to PI3P, two unique protein-binding systems are recruited and assembled to participate in the formation of autophagosomes: (1) ATG7 and ATG10 bind ATG5 to ATG12; ATG5 and ATG12 combine ATG16L1 to form an ATG5-ATG12-ATG16L1 complex. This complex binds to PI3P on the autophagic vesicles under the mediation of WIPI2B. (2) ATG7 and ATG3 bind LC3 (light-chain 3, ATG8) to the lipid phosphatidylethanolamine. LC3 is catalyzed by ATG4, which transforms it into the water-soluble form LC3-I. ATG7 and ATG3 combine with phosphatidylethanolamine on the autophagic vesicles with the mediation of ATG5-ATG12-ATG16L1 to convert LC3-I to the fat-soluble form LC3-II [34, 35]. LC3-II is usually considered the autophagosome marker [36, 37]: it is located on the autophagic vesicles and recruits several modification regulators to extend the autophagic vesicles. LC3-II can bind to a variety of cargo receptors, such as sequestosome-1 (SQSTM1/p62) and NBR1 (neighbor of BRCA1 gene 1) to promote the formation of autophagosomes [38-40]. Moreover, it promotes their binding to the substances that will be degraded, by bringing them into the autophagic vesicles for degradation [20].
A variety of ATG proteins bind to PAS and form an isolation membrane. ATG9 is an integrated membrane protein that can span multiple membranes, which binds to ATG2-WIPI on PAS with the mediation of FIP200. Membrane contact sites are then established to recruit downstream ATG proteins. Vesicles containing ATG9A provide the membrane structure for the growth of the autophagic vesicles [41]. Once the vesicles containing ATG9A fuse with PAS, the bowl-shaped cell membrane begins to extend and wrap part of the cytoplasm and organelles [42]. Finally, the isolation membrane forms a closed bilayer membrane structure with the mediation of ATG5-ATG12 and ATG8/LC3 binding systems. The substances and organelles that will be degraded are sealed inside. After all these steps, the autophagy vesicles mature into autophagosomes [43].
Fusion and Degradation of AutophagosomesOnce the autophagosome is formed in the cytoplasm, it is transported to the perinuclear region that is rich in lysosomes through microtubule and cytoskeleton dynamic proteins. Autophagosomes and lysosomes fuse when they are in close contact, with the coordination of V-ATPase, lysosomes-associated membrane protein (LAMP1), and many other proteins [44-46].
When the autophagosomes and lysosomes fuse into autolysosomes, the proteins and organelles that will be degraded into the autophagosomes are degraded by lysosome hydrolase. The degraded amino acids are recycled by cells through nutrient transporters [25]. The above-described mechanism is the primary molecular process of autophagy (Fig. 1).
Fig. 1.Mechanism of autophagy. When cells are subjected to nutritional stress, the negative regulator of autophagy mTORC1 is inhibited. The downstream autophagy initiation complex is activated, and a series of related proteins in the autophagy pathway are activated to initiate autophagy. When cells are under energy stress, the positive regulator AMPK is activated to promote the progress of autophagy through multiple signal transduction pathways.
Autophagy is the primary intracellular degradation system to deliver intracellular components to the lysosome for degradation. However, the role of autophagy is not only the simple elimination of cargo, but it also acts as a dynamic recycling system through the production of nutrients and energy for cell/tissue homeostasis. Autophagy also preserves immunity and prevents human diseases [47-49]. Indeed, it is an essential regulatory factor that keeps cardiovascular homeostasis in physiological conditions, preventing premature degenerative changes in cardiovascular tissues. Approaches have also been proposed to activate autophagy to limit the age-related physiological decline in heart function, which could also explain the close relationship between healthy lifestyles and autophagy activation, such as calorie restriction, physical exercise, and a low incidence of cardiovascular disease [50].
Autophagy is a key quality control mechanism, especially in nondividing cells such as neurons [51]. The retina is a light-sensitive tissue, which detects and transmits electric impulses through the optic nerve to the visual cortex in the brain. The function of both the retina and the eye is threatened by various environmental insults and stressors, such as genetic mutations and age-associated alterations. Autophagy is therefore acting to preserve retinal homeostasis and survival, playing an essential role in retinal development and cell differentiation [52, 53]. Studies found that the significant level of the autophagy-related protein LC3-II is linked to the time of the day in the retinal pigment epithelium cells. ATG5-deficient mice have decreased photoreceptor responses to light stimuli and decreased chromophore levels restored with exogenous retinoid supplementation. It is suggested that autophagy is essential for supporting normal vision [54]. These findings inspire scientists to consider the important role of autophagy in maintaining proper retinal function and the therapeutic potential of strategies targeting autophagy pathways to treat retinal and eye diseases.
Recent studies reported that autophagy plays a critical role in the normal function of pancreatic acinar cells and pancreatitis may occur when the autophagy pathway is disrupted. The genetic ablation of the essential autophagy proteins ATG5 and ATG7 in pancreatic epithelial cells causes the dysfunction of multiple organelles and spontaneous pancreatitis in mice [55]. Therefore, the maintenance of efficient autophagy in acinar cells prevents the onset and development of pancreatitis.
The expression of autophagic genes and proteins varies in different tissues and cells to maintain the normal function and homeostasis of various organs and prevent the abnormal proliferation of cells. The autophagic genes’ and proteins’ expression and function are listed in Table 1.
Table 1.The expression and function of autophagic genes and proteins in normal tissues
Autophagy is an important regulatory factor in tumor cells. Autophagic genes and proteins regulate critical factors in various pathological processes such as tumor cell growth, proliferation, differentiation, apoptosis, genomic instability, and immunity [56]. Their expression can be increased or decreased in various malignant tumors. Significant differences in the level of intracellular autophagy are present at different stages of tumor development [57]. The expression of the autophagic genes LC3 and ATG5 in different pathological stages of the intestinal-type gastric cancer is indeed modified. The LC3 and ATG5 mRNA expression gradually increases among the normal, intraepithelial neoplasia, and gastric cancer groups, and the differences among these groups are statistically significant [58]. This suggests that the level of autophagy changes during gastric cancer progression, providing essential materials for cancer cell proliferation and survival.
The expression of ATG proteins is decreased in cervical squamous cell carcinoma and a significant difference exists between cervical squamous cell carcinoma and high-grade cervical intraepithelial neoplasia or normal cervical epithelial cells. It is suggested that the level of autophagy is gradually downregulated during the development and progression of cervical cancer [59]. When intracellular autophagy is insufficient to remove the accumulation of abnormal proteins, it is difficult to maintain the homeostasis of cells. Abnormal cell proliferation will occur, which may lead to the occurrence and development of cancer. Human breast cancer cell lines exhibit the deletion of one or more Beclin-1 alleles and show decreased Beclin-1 levels compared to the normal adjacent tissue [60]. A total of 234 autophagy-related genes were obtained from The Human Autophagy Database for investigation. Among them, the differentially expressed autophagy-related genes were identified in prostate cancer patients based on The Cancer Genome Atlas (TCGA) database, including 5 upregulated genes (ATG9B, BIRC5, CAMKK2, CDKN2A, and NKX2-3) and 8 downregulated genes (DNAJB1, FAM215A, HSPB8, ITGB4, ITPR1, NRG1, NRG2, and TP63). Finally, the correlation between the autophagy-related genes and clinicopathological parameters such as age, tumor stages, Gleason score, overall survival, and disease-free survival was further analyzed. Prediction models based on autophagy-related genes were provided as a reliable prognostic and predictive tool for overall survival and disease-free survival in prostate cancer patients [61]. Different levels of autophagy in different tumor cells provide a clinical value in the diagnosis and prognosis of cancer and these genes represent potential targets for cancer treatment. Table 2 summarizes the expression and function of autophagic genes and proteins in different tumors.
Table 2.The expression and function of autophagic genes and proteins in different tumors
Since the term “autophagy” was first introduced in 1963, more and more in-depth understanding of the mechanism of autophagy was gained by the scientific community. Recent studies revealed the presence of various levels of autophagy in different cancers, such as lung cancer, breast cancer, and hepatocellular carcinoma [23, 62-65]. However, the role of autophagy in tumors is highly complex due to the differences in nutrients, microenvironmental pressure, pathogenic conditions, and immune ability [25]. Autophagy can inhibit or promote different types of tumors and the development of their various stages [66]. The regulatory role of autophagy in normal cells and tissues, tumor occurrence, growth and metastasis, and tumor treatment is shown in Figure 2.
Fig. 2.Regulation of autophagy. A certain level of autophagy is of great significance for maintaining cell homeostasis, but the abnormal level of autophagy can participate in the regulation of tumor progression and affect the occurrence and reversal of anticancer treatment resistance. The specific regulatory mechanism is shown in the figure.
Autophagy plays quality control in the early stage of tumorigenesis. It promotes the degradation of carcinogenic factors by clearing the abnormally folded or aggregated proteins and the damaged organelles [65]. Then, it maintains the stability of the cell genome. Autophagy inhibits tumor growth by preventing tumor proliferation, invasion, and metastasis [67, 68].
The expression of the autophagy-associated protein Beclin-1 gradually decreases in normal cervical tissues, cervical intraepithelial neoplasia tissues and cervical cancer tissues. In contrast, the expression of autophagy-associated proteins is further inhibited during the occurrence and development of cervical cancer [69-71]. These results suggest that the level of autophagy tends to decrease in the progress of cervical cancer, and autophagic genes can act as tumor suppressor genes. The animal model of autophagy deficiency led to a similar conclusion. The knockout of Beclin1 and ATG7 in mice causes a significant increase in spontaneous tumors, indicating the inhibitory effect of autophagy on tumorigenesis [72]. Mice with ATG5 and ATG7 deletion are prone to liver tumors, and tumor cells are derived from autophagy-deficient hepatocytes [73]. Cell proliferation and the occurrence of cancer increase, and the development of carcinogen-induced premalignant lesions accelerates when autophagy is inhibited, or BECN1 is disrupted [60]. These studies on the occurrence and development of tumors caused by the defects of these autophagy-related proteins and genes support the view that autophagy inhibits tumorigenesis.
Promotion of Tumor Progression by AutophagyAlthough some scholars believe that autophagy inhibits tumorigenesis by promoting the degradation of carcinogens and maintaining the stability of cell genomes, many studies also found that autophagy can be induced when cells are subjected to adverse environmental factors to supply the cells with the energy substances to help them cope with hypoxia, nutritional deficiency, and various traumatic stimuli through the cycle of nutrients. In this way, autophagy can promote cancer progression by ensuring tumor cells’ survival [74]. The tumor tissue may face hypoxia and energy deficiency due to insufficient vascular establishment since tumor cells proliferate rapidly and nutrients are obstacles to being readily available [66]. Therefore, autophagy is believed to maintain the energy supply, enhance the ability to tolerate stress, and prevent the death of tumor cells [75].
Liu et al. [76] found that autophagy enhances the activation of the STAT3/ERK pathway and promotes the survival and proliferation of colonic epithelial cells during the development of colitis-associated cancer, suggesting that autophagy can prevent drug-induced epithelial cell damage and promote tumorigenesis. Autophagy ensures tumor cell survival and proliferation by providing nutrients to cancer cells and maintains the cancer phenotype by regulating tumor metabolism [77, 78]. A variety of metabolic raw materials such as amino acids, nucleotides, and fatty acids produced by autophagy are provided to tumors to improve their metabolism and enable them to grow and survive well in severe microenvironments [75, 79].
In addition to promoting tumor progression through the above two aspects, the latest research also focuses on its effects on tumor cell invasion and migration [80-82]. Indeed, autophagy provides power to tumor cells to make them able to migrate and invade [83-85]. Sharifi et al. established ATG5- and ATG7-deficient breast cancer murine models. They found that autophagy-deficient mice have significantly less lung and liver metastasis than normal mice, suggesting that autophagy inhibition reduces the migration and invasion of tumor cells in vitro and decreases the metastasis of tumor cells in vivo [86]. The bidirectional regulation of autophagy in tumorigenesis and development enlightens whether we can use this contradictory mechanism to treat cancer or improve the efficacy of anticancer therapy.
Cell Autophagy and Treatment of CancerAutophagy plays an essential role in normal and cancer cells, but cancer cells depend more on autophagy [23, 87]. Therefore, many processes involved in tumorigenesis and tumor treatment can be regulated by changing the level of autophagy in tumor cells. The inhibition or promotion of autophagy affects tumor growth, proliferation, and drug resistance and reverses the resistance of drug-resistant cancer cells to chemotherapeutic drugs [9, 79, 88, 89]. If properly regulated, autophagy can be used to enhance the effect of chemotherapy and improve cancer treatment. In addition, radiotherapy, chemotherapy, and physiotherapy can cause metabolic stress and the activation or inhibition of autophagy [4, 90]. Therefore, researchers considering autophagy as a focus of anticancer therapy should explore the effective autophagy activators or inhibitors depending on the type of cancer or cancer treatment due to the dual regulatory role of autophagy in cancer to obtain an improvement of the therapeutic effect.
Inhibition of Autophagy in Cancer TherapyAnticancer drugs and radiation can induce autophagy in cancer cells providing them with the basic substances for survival and metabolism to avoid apoptosis, thus reducing the effect of anticancer drugs and inducing drug resistance [91]. Therefore, the researchers want to explore whether the inhibition of autophagy leads to the inhibition of the occurrence of drug resistance or increased sensitivity of tumor cells to anticancer drugs.
Since then, various autophagy inhibitors have been used in experimental studies, which inhibit autophagy by targeting the activation of critical proteins in the autophagy pathway. For example, chloroquine (CQ) and hydroxychloroquine (HCQ) inhibit the final step of autophagy by damaging the function of lysosomes and blocking the fusion of autophagosomes and lysosomes [92-94]. The drug 3-methyladenine (3-MA) suppresses autophagy by inhibiting the Beclin1-VPS34 (PI3K) complex, which is upstream of the autophagy pathway [18]. In addition, the ULK1 inhibitors [95, 96] and the ATG4 inhibitors [97-99] exert antitumor activity in vivo and in vitro. Among them, CQ and HCQ are the most studied, and their ability to inhibit autophagy and its tolerance in combination with other anticancer drugs have been confirmed by stage 1 clinical trials [100]. Further studies combining different anticancer drugs and autophagy inhibitors in cancer patients are needed, which is helpful to explore whether autophagy inhibitors combined with anticancer drugs can better improve anticancer efficacy and serve as one of the effective strategies for advanced cancer treatment [101, 102].
Anticancer therapy faces great challenges due to the development of chemotherapy resistance. Cisplatin promotes the formation of autophagic vesicles, increases the transformation of LC3-I to LC3-II, upregulates the expression of the autophagy-related protein Atg7, and then induces autophagy in HeLa cells [103]. The sensitivity of HeLa cells to cisplatin increases when the occurrence of autophagy is inhibited by 3-MA [104, 105]. Similarly, 20(S)-ginsenoside Rh2 (GRh2) and apigenin inhibit the AKT/mTOR signaling pathway in cancer cells and induce autophagy, while the pretreatment with 3-MA enhances the apoptosis induced by 20(S)-GRh2, suggesting that 20(S)-GRh2-induced autophagy protects cancer cells from apoptosis, working as a survival mechanism, and apoptosis and autophagy cooperatively induce cell death [106-108]. Angelicin is a natural molecule isolated from the traditional Chinese herb Angelica archangelica, which has anticancer activity [109]. Wang et al. [110] found that angelicin induces mTOR phosphorylation in cancer cells and reduces the expression of the autophagy-related proteins Atg3, Atg7, Atg5, and Atg12, exerting an anticancer activity. This evidence indicates that angelicin inhibits the malignant behavior of cervical cancer through the suppression of autophagy. The natural plant extract Kazinol C induces apoptosis of colon cancer cells by activating AMPK. The knockout of ATG5 or 3-MA to block autophagy enhances Kazinol C-induced apoptosis [111]. These findings may provide a rationale for future clinical applications using molecules with anticancer activity combined with autophagy inhibitors.
Autophagy maintains cell survival through nutrient circulation, and proper autophagy protects cells against death, but excessive autophagy can lead to apoptosis [112]. Hence, autophagy in tumor cells can be inhibited to block the nutrition and energy supply of cancer cells, so that cancer cell viability and proliferation are inhibited when facing nutrition or energy deficiency, they are prone to apoptosis and necrosis, and tumor growth is finally inhibited. Therefore, it is necessary to explore the tumors that are sensitive to autophagy inhibitors to use them as anticancer therapy.
Promotion of Autophagy in Anticancer TherapyAlthough preclinical trials and clinical trials confirmed that the combination of autophagy inhibitors CQ and HCQ with chemotherapeutic drugs significantly improves the efficacy of anticancer therapy [93], the latest studies found that many traditional Chinese medicines and naturally derived compounds with anticancer activities activate autophagy-related pathways, thus increasing the level of autophagy and inducing autophagy-related death in cancer cells [113].
Autophagy induces apoptosis of cancer cells, thus potentially representing a mechanism of anticancer therapy. Moreover, chemotherapy drug resistance is closely related to apoptosis. Based on this, many scholars start to explore whether a high level of autophagy can affect the drug resistance of cancer cells. Zhai et al. [114] showed that astragalus polysaccharide upregulates the expression of Beclin1 in cervical cancer cells, promotes the transformation of LC3-I to LC3-II, and enhances autophagic activity. This effect increases the sensitivity of cervical cancer cells to cisplatin chemotherapy. Naringenin activates AMPK signaling pathway, enhances autophagy, and reverses the resistance of cervical cancer cells to cisplatin by inhibiting cell proliferation and promoting apoptosis [115]. The naturally derived compound rosmarinic acid methyl ester increases the mRNA expression of autophagy-related genes (ULK1, ATG5, BECN1, ATG7, ATG12, and ATG13) and induces autophagy and apoptosis in cancer cells. The combination treatment of rosmarinic acid methyl ester and cisplatin greatly enhances the antitumor effect in cisplatin-resistant cervical and ovarian cancer cells, which is due to autophagy and apoptosis mediated by the inhibition of the mTOR/S6K1 signaling pathway [116, 117].
Autophagy is a multifactor-regulated process. Transcription factor EB (TFEB) is known as a regulator of autophagy and lysosomal biogenesis is involved in various human diseases, such as neurodegenerative diseases, metabolic disorders, and cancers [118, 119]. It can be negatively regulated by mTOR [120, 121]. The use of Qingyangshen, Chinese herbal medicine, can activate PPARα-TFEB to promote the autophagy and autophagy-lysosomal pathway for the clearance of amyloid β plaques and Tan aggregates and play its neuroprotective effects [122]. In addition to the research on neurodegenerative diseases, targeting TFEB to regulate autophagy has become one of the hot topics in cancer research in recent years [123, 124]. Fucoidan is a marine-origin sulfated polysaccharide that has anticancer activities. Zhang et al. found that fucoidan induced autophagy in breast cancer cells by down-regulating mTOR/p70S6K/TFEB pathway, thus inhibiting tumor development. At the same time, they also explored the chemotherapeutic sensitization of fucoidan and concluded that fucoidan might enhance the sensitivity of breast cancer cells to chemotherapeutic drugs doxorubicin and cisplatin [125]. These findings will help researchers to further explore the regulatory role of TFEB in cancers as one of the effective targets for anticancer therapy.
In addition to the effect on drug resistance of cancer cells, excessive autophagy also inhibits cell proliferation and growth and induces autophagic death or autophagy-related death. The natural drug 1-(2-hydroxy-5-methylphenyl)-3-phenyl-1,3-propanedione (HMDB) induces the expression of LC3 and Beclin-1, thus triggering autophagy in cells and inhibiting their growth [126]. Ursolic acid (UA) is a natural pentacyclic triterpene carboxylic acid that induces autophagy in cancer cells through the upregulation of the autophagy-related protein ATG5 without inducing apoptosis, and its ability to induce autophagy is not affected by BECN1. This new finding of UA effects suggests that UA can be used as a complementary therapy when patients are not sensitive to the anticancer drugs that induce apoptotic cell death [127]. Pyoluteorin is a naturally occurring antibiotic that exerts its antitumor effects on human non-small cell lung cancer cells by the upregulation of the accumulation of LC3 to induce autophagy. In addition, pyoluteorin induces autophagy through the activation of the c-Jun N-terminal kinase/B-cell lymphoma-2 (JNK/Bcl-2) signaling pathway. When the JNK/Bcl-2 pathway is blocked, the pyoluteorin-induced autophagy is significantly reduced. The combination of pyoluteorin with the autophagy inhibitor 3-MA significantly promotes human non-small cell lung cancer cell death and therefore can be considered as a potential anticancer strategy in lung cancer therapy [128]. Betulin is a naturally occurring pentacyclic triterpene with several pharmacologic effects, such as anti-inflammatory, antiosteoclastogenic, antiamnesic, and anticancer properties. Betulin suppresses the lung metastasis of colorectal cancer cells by inducing autophagy through the activation of AMPK and PI3K/Akt/mTOR signaling pathways. Therefore, betulin has an antimetastatic effect and therapeutic potential in metastatic colorectal cancer and can be considered as a novel therapeutic agent targeting autophagy [129]. Likewise, gallotannin also inhibits colorectal cancer metastasis by activating AMPK and PI3K/Akt/mTOR signaling pathways [130]. Therefore, the induction of high levels of autophagy in cancer cells may be an effective complementary cancer therapy.
Physiotherapy low-intensity ultrasound induces cell apoptosis without causing cell necrosis and it is increasingly used in tumor therapy [131], thus providing a new idea for the synergistic treatment of cancer. Many studies showed that low-intensity ultrasound affects the expression of autophagy-related proteins and genes and induces autophagic cell death by inhibiting the activity of mTOR signaling pathway [132, 133]. However, the specific molecular mechanism is not yet completely clear. Low-intensity ultrasound combined with radiofrequency ablation significantly upregulates the expression of ATG5 and Beclin1 in pancreatic cancer cells, exerting anticancer effects by enhancing the autophagy of these cells and inducing their autophagic death [134]. In addition, low-intensity ultrasound induces autophagy and autophagy-dependent cell death by the upregulation of the expression of Beclin-1, ATG5, and LC3-II in prostate cancer cells as well [135, 136]. The mechanism of various molecules targeting autophagy in different tumors is shown in Table 3.
Table 3.The mechanism of various molecules targeting autophagy in different tumors
In normal tissues and cells, the level of autophagy is low and stable, which can maintain cell homeostasis through the degradation of abnormally accumulated proteins and damaged organelles. Under the action of various physiological and pathological factors, the level of autophagy changes to cope with these stimuli and help the body through the period of homeostasis disorder. When cells in the body proliferate abnormally and become cancerous, the level of autophagy in the cells will undergo permanent and stable changes. The role of autophagy in cancer is very complex since it can promote or inhibit the survival of cancer cells. In recent years, many scholars devoted themselves to the study of the mechanism of action of anticancer drugs and their effect by inhibiting the occurrence and the level of autophagy, and some scientists studied the clinical anticancer effect of combining chemotherapeutic drugs with autophagy inhibitors. Some other researchers also focused their attention on the sensitivity of tumor cells to chemotherapeutic drugs by changing the level of intracellular autophagy. More and more studies are available on the induction of autophagy for anticancer therapy due to the more and more in-depth study of traditional Chinese medicine and natural medicinal plants, but its specific mechanism and safety need to be further explored. In addition, further study of autophagy may reveal its inhibition as an effective way to inhibit the metastatic spread of clinical malignant tumors. This prompts researchers to conduct more detailed studies in this field.
The level of autophagy is different in various types of tumors. Therefore, it is of utmost importance to systematically explore which types of tumors are suitable for the inhibition of autophagy to improve the anticancer effect and which are suitable for the promotion of the level of autophagy. It is also important to explore changes in autophagy levels at different stages of tumor development to more effectively inhibit the proliferation, migration, and invasion of tumor cells. Only a full understanding of the bidirectional regulation of autophagy may lead to the development of efficient, specific, and safe autophagy inhibitors or inducers. Given the important regulatory role of autophagy in cancer, specific links in the process of autophagy or specific proteins in the autophagy pathway can be targeted to change the level of autophagy in cancer cells, to better improve the anticancer efficacy, and to extend to clinical application. The knowledge of its mechanism may be used to treat different types of tumors at different stages and provide theoretical guidance for effective clinical anticancer therapy.
Conflict of Interest StatementThe authors have no conflicts to declare.
Funding SourcesThis work was supported by National Natural Science Foundation of China (No. 81860328), the Science and Technology Planning Project of Guizhou Province (Nos. QKHZC[2020]4Y161 and QKHZC[2022]194); and the main projects of the Natural Science Foundation of Guizhou province (No. QKHJC-ZK[2022]ZD031).
Author ContributionsConceptualization: Ting Zhang and Juan Qin; collection the literature: Ting Zhang, Jia Yu, Sha Cheng, Ya Zhang, and Chang-hua Zhou; writing – original draft preparation: Ting Zhang and Juan Qin; writing – review and editing: Juan Qin and Heng Luo; and project administration: Heng Luo. All authors have read and agreed to the published version of the manuscript.
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