Sensitization of colon cancer cells to cisplatin by Fbxw7 via negative regulation of the Nox1-mTOR pathway

Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality worldwide [1]. Moreover, a number of advanced colon cancer patients developed metastasis to other organs such as liver and lung [2]. Consequently, the survival rates of CRC patients remain low [3]. Currently, surgical resection is the main therapy for colorectal cancer, while chemo- or radio- therapy is routine approach for CRC patients with advanced or metastatic tumors [4]. Cisplatin (CDDP) is a platinum derivative, widely used chemotherapeutic anti-cancer agent against diverse cancer types through inducing DNA lesions and causing cell cycle arrest and apoptosis of cancer cells [5]. Despite the initial effectiveness in clinical application of cisplatin, a number of colon cancer patients developed cisplatin resistance, leading to tumor recurrence and consequently therapeutic failures [6]. Therefore, understanding the precise molecular mechanisms underlying the intrinsic and acquired CDDP resistance is an urgent task for improving prognosis of CRC patients.

The F-box and WD repeat domain-containing 7 (Fbxw7), which serves as a substrate recognition subunit of E3 ubiquitin ligase, mediates its target proteins degradations without affecting transcriptions through direct binding with targets proteins [7]. Since accumulating oncogenic proteins have been revealed to be negatively regulated by Fbxw7 through direct targeting such as Cyclin E, c-Jun, c-Myc, Notch, SREBPs, Aurora-A and TGIF1 [8], Fbxw7 was known as a tumor suppressor in CRC tissues [9]. Downregulated Fbxw7 was associated with tumor progressions and poor prognosis [10]. Therefore, identification of Fbxw7 targets provides a promising strategy for development of therapeutic targets against colon cancer.

Nox1 (superoxide-generating NADPH oxidase 1) which involves in the productions of ROS, is a member of the Nox enzyme family [11]. Nox1 was upregulated in colon tumors and contributed to progressions of colon cancer [12]. Recent studies revealed that Nox1 and mTORC1 co-localized in colon cancer spheroids and Nox1 activated mTOR1 activity through direct oxidation of S100A9, leading to stimulating the proliferation of colon cancer cells via mTORC1 activation [13]. Moreover, Fbxw7 was known as a negative regulator of mTOR signaling in CRC [14], suggesting Fbxw7 might block mTOR activity through association of Nox1. However, the biological functions of Fbxw7-Nox1 interaction in regulating CRC progression remains largely unknown. Here, we aimed to investigate the Fbxw7-dependent regulatory pathways involved in cisplatin resistance of CRC. The association between Fbxw7-Nox1 will be assessed and the downstream regulatory effects on the mTORC1 activation, leading to sensitization of CRC cells to cisplatin. Our study potentiates the Fbxw7-Nox1-mTOR axis as a novel target to enhance the anti-tumor effects of chemotherapeutic agents.

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