FBXW7 and human tumors: mechanisms of drug resistance and potential therapeutic strategies

Abstract

Drug therapy, including chemotherapy, targeted therapy, immunotherapy, and endocrine therapy, stands as the foremost therapeutic approach for contemporary human malignancies. However, increasing drug resistance during antineoplastic therapy has become a substantial barrier to favorable outcomes in cancer patients. To enhance the effectiveness of different cancer therapies, an in-depth understanding of the unique mechanisms underlying tumor drug resistance and the subsequent surmounting of antitumor drug resistance is required. Recently, F-box and WD Repeat Domain-containing-7 (FBXW7), a recognized tumor suppressor, has been found to be highly associated with tumor therapy resistance. This review provides a comprehensive summary of the underlying mechanisms through which FBXW7 facilitates the development of drug resistance in cancer. Additionally, this review elucidates the role of FBXW7 in therapeutic resistance of various types of human tumors. The strategies and challenges implicated in overcoming tumor therapy resistance by targeting FBXW7 are also discussed.

Transcriptional Up-Regulation of FBXW7 by KCa1.1 K+ Channel Inhibition through the Nrf2 Signaling Pathway in Human Prostate Cancer LNCaP Cell Spheroid Model

“…The loss of the E3 ubiquitin ligase, FBXW7 synergizes with the acquisition of stemness and anti-cancer resistance and the accumulation of pluripotent transcription factors, such as c-Myc in cancer cells [ 8 , 9 , 11 ]. We recently reported that the inhibition of K Ca 1.1 overcame chemoresistance by down-regulating drug-metabolizing enzymes through the Akt-Nrf2 signaling pathway in 3D cancer spheroid models [ 2 ].…”

“…The percentage of cells We recently reported that the inhibition of K Ca 1.1 suppressed the Akt-Nrf2 signaling pathway by reducing the phosphorylation level of Akt in the LNCaP spheroid model [2]. Wang et al indicated that activated Akt down-regulated FBXW7 in cancer cells [11]. To elucidate whether the K Ca 1.1 inhibition-induced up-regulation of FBXW7 is mediated through the Akt/Nrf2 signaling pathway, we examined the effects of the Akt activator, SC79, and the Nrf2 activator, NK252, on it in the LNCaP spheroid model.…”

“…In prostate cancer, up-regulated FBXW7 also suppresses the expressions of c-Myc and Notch-1 [ 10 ]. In addition, FBXW7 plays an important role in the modification of sensitivity to anti-cancer drugs in cancers, including prostate cancer [ 11 ]. We previously identified FBXW7 as an essential regulator of K Ca 1.1 protein degradation in several cancers [ 5 , 6 , 12 ] and showed that the down-regulated expression of FBXW7 by cancer spheroid formation increased K Ca 1.1 activity by promoting its protein level in the plasma membrane [ 5 , 6 ].…”