Role of FoxO Proteins in Cellular Response to Antitumor Agents

Abstract

FoxO proteins (FoxOs) are transcription factors with a common DNA binding domain that confers selectivity for DNA interaction. In human cells, four proteins (FoxO1, FoxO3, FoxO4 and FoxO6), with redundant activity, exhibit mainly a positive effect on genes involved in cell cycle, apoptosis regulation and drug resistance. Thus, FoxOs can affect cell response to antitumor agent treatment. Their transcriptional activity depends on post-translational modifications, including phosphorylation, acetylation, and mono/poly-ubiquitination. Additionally, alterations in microRNA network impact on FoxO transcripts and in turn on FoxO levels. Reduced expression of FoxO1 has been associated with resistance to conventional agents (e.g., cisplatin) and with reduced efficacy of drug combinations in ovarian carcinoma cells. FoxO3 has been shown as a mediator of cisplatin toxicity in colorectal cancer. A requirement for FoxO3-induced apoptosis has been reported in cells exposed to targeted agents (e.g., gefitinib). Recently, the possibility to interfere with FoxO1 localization has been proposed as a valuable approach to improve cell sensitivity to cisplatin, because nuclear retention of FoxO1 may favor the induction of pro-apoptotic genes. This review focuses on the role of FoxOs in drug treatment response in tumor cells and discusses the impact of the expression of these transcription factors on drug resistance/sensitivity.

Polymerase independent repression of FoxO1 transcription by sequence-specific PARP1 binding to FoxO1 promoter

“…On the one hand, FoxO1 inhibits cancer cell proliferation by activating the transcription of p21, encoding a cell cycle inhibitor 26 ; on the other, FoxO1 induces apoptosis by upregulating expression of several pro-apoptotic factors including PUMA and Bim 26,34 . Moreover, FoxO1 also affects cellular sensitivity or resistance to anticancer drugs 26,28,[34][35][36] . Though its posttranscriptional modifications and its transcriptional control of target genes have been extensively investigated 37 , relatively little is known about transcriptional regulation of the FoxO1 gene itself.…”

Expression of Adenoviral E1A in Transformed Cells as an Additional Factor of HDACi-Dependent FoxO Regulation

“…Several lines of evidence suggest a critical role for FoxO members in the sensitivity of cancer cells to cytotoxic agents. Reduced expression of FoxO1 and FoxO3 is associated with resistance to conventional agents and with reduced efficacy of drug combinations in ovarian and breast cancer cells [64][65][66]. FoxOs play an important role in apoptosis by activating transcription of the ligand for the Fas-dependent cell death pathway FasL, and the proapoptotic Bcl-2 family member Bim.…”

Mechanisms of tRNA-derived fragments and tRNA halves in cancer treatment resistance

“…FoxO proteins have been reported to affect the effectiveness of anticancer drug treatment. Reduced FoxO1 expression is related to resistance to cisplatin [158]. To summarize, these differentially expressed tRFs affect the sensitivity of OC to chemotherapy, especially to cisplatin.…”