General information

In this study, with the aid of the quantitative analysis program VOSviewer, we examined the findings and advancements in the study of the function of sgk1 in cancer. A quantitative analysis is conducted on the fundamental data on the annual publishing quantity, country, author, institution, and journal. It is possible to identify essential countries/regions and research institutions that have published numerous documents related to this topic, have more significant influence, and determine their cooperative relationship based on the statistical analysis of the number of papers published by various countries/regions and institutions. Eberhard Karls Universität Tübingen has the most publications among the ten best institutions. Of the top 10 authors, Lang, F. had the most published articles (135 papers), followed by Alesutan, I. (33 papers). According to the journal distribution in Table 1, the International Journal of Molecular Sciences has the highest number of publications on this topic, followed by PLoS ONE.

The hot spots and frontiers

Based on cluster analysis of keywords and timeline viewer, the current research hot spots on the role of SGK1 in cancer are mainly categorized into four aspects: upregulation of SGK1 as a prognostic marker, cellular mechanisms underlying SGK-1's role in cancer progression and survival, resistance to therapy, and current strategies to target SGK-1 in cancer therapy.

Upregulation of SGK-1 in Cancer

Several studies have reported elevated expression levels of SGK-1 in different cancer types. The upregulation of SGK-1 has been associated with various cellular processes involved in cancer development and progression. SGK-1 has been implicated in promoting cell survival, proliferation, and resistance to apoptosis, which are characteristics of cancer cells. Ronchi et al. reported that SGK-1 is upregulated in adrenocortical adenomas [15]. Wu et al.'s research on breast cancer indicates that the inactivation of FOXO3a through glucocorticoid receptor (GR)-mediated induction of SGK-1 expression leads to enhanced tumor cell proliferation [16]. This impact is shown in SK-BR-3 breast tumor cells, where apoptosis mediated by FOXO3a is significantly reduced by SGK1 activation.

Moreover, SGK1 expression is increased in hypoxic breast cancer cells, promoting cell survival [17]. A study conducted by Liu et al. suggested that SGK1 is commonly expressed in normal human prostate tissue, but exhibits increased expression in prostate cancer tissues, particularly in metastatic cases. This association implies that SGK1 expression may play a role in the progression of prostate tumors [18]. Schmid et al. highlighted that SGK1 mRNA expression is notably higher in alveolar rhabdomyosarcoma tissues compared to muscle tissue, and it is significantly lower in embryonal rhabdomyosarcoma. Furthermore, the RH30 rhabdomyosarcoma cell line exhibited more SGK1 transcripts than the RD. These findings suggest a potential role for SGK1 in the molecular characteristics of rhabdomyosarcoma and point toward differences in SGK1 expression between alveolar and embryonal subtypes as well as between distinct rhabdomyosarcoma cell lines [19].

SGK1 as a multifaceted prognostic marker across various cancer types: insights from recent studies

Serum and glucocorticoid-regulated kinase 1 (SGK1) has recently been the subject of much discussion due to its potential use as a prognostic marker for various cancers. SGK1 overexpression in tissue can predict cancer development and a worse prognosis for individuals with non-small cell lung cancer (NSCLC), according to a study by Abbruzzese et al. [20]. Tang et al.'s substantial prognostic value of higher SGK1 expression, which correlates with worse overall survival in NSCLC patients, is consistent with their findings [4]. Moreover, studies on esophageal squamous cell carcinoma highlighted the critical role that SGK1 plays in patient outcomes. Compared to the low-expression group, high SGK1 expression was linked to significantly shorter overall and disease-free survival, highlighting its potential as a prognostic indicator in this particular cancer subtype [21]. Serum Lnc-SGK1 expression plus H. pylori infection were a significant predictive factor in gastric cancer, indicating its potential use as a diagnostic marker.

On the other hand, glioblastoma multiform investigations demonstrated a complex association: Fewer segments of the SGK1 gene were linked to a worse overall survival rate, but more segments were connected with a higher overall survival rate, which may be related to greater tumor oxygenation [3]. Research on adrenocortical carcinoma has demonstrated the independent predictive significance of SGK1 protein levels, regardless of glucocorticoid production and tumor stage. Szmulewitz et al.'s prostate cancer studies highlighted the complex connection between SGK1 staining, cancer grade, and recurrence risk, highlighting its potential as a multidimensional prognostic marker [22].

Cellular mechanisms underlying SGK-1's role in cancer progression and survival

In Fig. 10, we can see how SGK1 promotes cancer cell survival, and here is a detailed description for each point: anti-apoptotic proteins: SGK-1 phosphorylates and inactivates pro-apoptotic proteins such as BAD (Bcl-2-associated death promoter). By phosphorylating BAD, SGK-1 prevents its interaction with the anti-apoptotic protein Bcl-2, thereby inhibiting apoptosis. This mechanism promotes cell survival by suppressing the activation of the intrinsic apoptotic pathway [23].

Fig. 10

Role of SGK1 in enhancing cancer cell survival through key regulatory mechanisms

Pro-survival pathways SGK-1 activates pro-survival pathways such as the PI3K/Akt pathway. Upon activation, Akt phosphorylates and inhibits several pro-apoptotic factors, including caspase-9 and members of the Bcl-2 family. In addition to directly inhibiting apoptosis, Akt activation by SGK-1 promotes cell survival by stimulating cell growth, proliferation, and metabolism through downstream targets such as mTOR (mechanistic target of rapamycin) and FOXO transcription factors [24].

Cell cycle progression: SGK-1's role in cell cycle regulation and tumor cell proliferation

SGK-1 promotes cancer cell proliferation by influencing cell cycle progression, particularly at the G1/S transition. It does so by phosphorylating and stabilizing cyclin D1, a critical regulator of the G1 phase of the cell cycle. Stabilization of cyclin D1 by SGK-1 enhances its interaction with cyclin-dependent kinases (CDKs), leading to increased retinoblastoma protein (Rb) phosphorylation and subsequent progression through the G1 phase. This cell cycle acceleration promotes tumor cell proliferation and survival by facilitating rapid cell division and growth [25].

DNA repair: SGK-1-mediated DNA damage response and genomic stability

SGK-1 plays a role in the DNA damage response and the maintenance of genomic stability, thereby promoting cancer cell survival. Upon DNA damage, SGK-1 is activated and phosphorylates various proteins involved in DNA repair pathways. For example, SGK-1 phosphorylates and activates BRCA1 (breast cancer gene 1), an essential protein in homologous recombination repair of DNA double-strand breaks. SGK-1 also phosphorylates and activates RAD51, another essential protein in homologous recombination repair. By enhancing the activity of these DNA repair proteins, SGK-1 promotes the efficient repair of DNA damage, thereby preventing the accumulation of mutations and genomic instability that could otherwise trigger apoptosis or contribute to tumor progression [26].

SGK-1's contribution to resistance against different cancer therapies

It was noted that the reduction of SGK-1 is related to a poor prognosis in adrenocortical carcinoma in a few studies, contrary to the most recent show that multiple types of tumors such as colon, breast, prostate, and other types exhibit higher levels of SGK-1 than normal tissue [27]. Table 2 provides a comprehensive overview of various cancer types, their prevalence, the role of SGK-1 (serum and glucocorticoid-regulated kinase 1) in each cancer, treatment mechanisms, and corresponding references.

Table 2 Cancer types, prevalence, SGK-1 involvement, and treatment mechanismsChemotherapy resistance: SGK-1's influence

The study conducted by Talarico et al. revealed the function of SGK1 in chemo-resistance. They demonstrated that ectopic IL-2 receptor expression in renal cancer cells might trigger SGK1 activation via PI3K. In addition to promoting hyper-proliferation and survival, activated SGK1 also creates resistance to doxorubicin via a mechanism that depends on FAS/FASL (CD95–CD95L) (34).

Radiotherapy resistance: SGK-1 modulation

There is a correlation between MDM2-dependent p53 degradation and the in vivo expression of SGK1. Mice subjected to prolonged restraint stress, which activates the hypothalamic–pituitary–adrenal axis, showed increased expression of SGK1. In addition to significantly promoting ionizing radiation (IR)-induced carcinogenesis in p53 ± mice, activated SGK1 also boosted MDM2-mediated p53 degradation and accelerated the development of human xenograft tumors.

By activating MDM2, it was established that SGK1 was a crucial negative regulator of p53. In a colon cancer (CaCo-2) cell line, modest doses of radiation (3GY) combined with pharmacological inhibition of SGK1 by EMD638683 (50 µM) resulted in mitochondrial depolarization, late apoptosis (necro-apoptosis), and a relative increase in caspase-3 [34]. The concurrent administration of an SGK1-specific inhibitor (EMD638683) enhances TAC's effects and works in concert with radiation treatment. The authors conclude that mAR activation, along with radiation and SGK1 suppression, may offer a potent new anti-tumorigenic tactic in the fight against breast cancer [35].