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Supplementary Figure Legends, Figures 1 - 4 from Regorafenib Inhibits Colorectal Tumor Growth through PUMA-Mediated Apoptosis

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posted on 2023-03-31, 17:29 authored by Dongshi Chen, Liang Wei, Jian Yu, Lin Zhang

PDF file - 301KB, Figure S1. Potential roles of transcription factors in PUMA induction by regorafenib in CRC cells. Figure S2. p65 mediates PUMA induction by regorafenib in CRC cells. Figure S3. PUMA-dependent chemosensitization by regorafenib in CRC cells. Figure S4. PUMA-dependent chemosensitization by regorafenib in xenograft tumors.

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ARTICLE ABSTRACT

Purpose: Regorafenib, a multikinase inhibitor targeting the Ras/Raf/MEK/ERK pathway, has recently been approved for the treatment of metastatic colorectal cancer. However, the mechanisms of action of regorafenib in colorectal cancer cells have been unclear. We investigated how regorafenib suppresses colorectal cancer cell growth and potentiates effects of other chemotherapeutic drugs.Experimental Design: We determined whether and how regorafenib induces the expression of PUMA, a p53 target and a critical mediator of apoptosis in colorectal cancer cells. We also investigated whether PUMA is necessary for the killing and chemosensitization effects of regorafenib in colorectal cancer cells. Furthermore, xenograft tumors were used to test if PUMA mediates the in vivo antitumor, antiangiogenic, and chemosensitization effects of regorafenib.Results: We found that regorafenib treatment induces PUMA in colorectal cancer cells irrespective of p53 status through the NF-κB pathway following ERK inhibition and glycogen synthase kinase 3β activation. Upregulation of PUMA is correlated with apoptosis induction in different colorectal cancer cell lines. PUMA is necessary for regorafenib-induced apoptosis in colorectal cancer cells. Chemosensitization by regorafenib is mediated by enhanced PUMA induction through different pathways. Furthermore, deficiency in PUMA abrogates the in vivo antitumor, antiangiogenic, and chemosensitization effects of regorafenib.Conclusions: Our results demonstrate a key role of PUMA in mediating the anticancer effects of regorafenib in colorectal cancer cells. They suggest that PUMA induction can be used as an indicator of regorafenib sensitivity, and also provide a rationale for manipulating the apoptotic machinery to improve the therapeutic efficacy of regorafenib and other targeted drugs. Clin Cancer Res; 20(13); 3472–84. ©2014 AACR.