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- W4361238662 abstract "<div>Abstract<p>Mitochondria are the powerhouses of cells. Mitochondrial C-Raf is a potential cancer therapeutic target, as it regulates mitochondrial function and is localized to the mitochondria by its N-terminal domain. However, Raf inhibitor monotherapy can induce S338 phosphorylation of C-Raf (pC-Raf<sup>S338</sup>) and impede therapy. This study identified the interaction of C-Raf with S308 phosphorylated DAPK (pDAPK<sup>S308</sup>), which together became colocalized in the mitochondria to facilitate mitochondrial remodeling. Combined use of the Raf inhibitors sorafenib and GW5074 had synergistic anticancer effects <i>in vitro</i> and <i>in vivo</i>, but targeted mitochondrial function, rather than the canonical Raf signaling pathway. C-Raf depletion in knockout MEF<sup>C-Raf−/−</sup> or siRNA knockdown ACHN renal cancer cells abrogated the cytotoxicity of combination therapy. Crystal structure simulation showed that GW5074 bound to C-Raf and induced a C-Raf conformational change that enhanced sorafenib-binding affinity. In the presence of pDAPK<sup>S308</sup>, this drug–target interaction compromised the mitochondrial targeting effect of the N-terminal domain of C-Raf, which induced two-hit damages to cancer cells. First, combination therapy facilitated pC-Raf<sup>S338</sup> and pDAPK<sup>S308</sup> translocation from mitochondria to cytoplasm, leading to mitochondrial dysfunction and reactive oxygen species (ROS) generation. Second, ROS facilitated PP2A-mediated dephosphorylation of pDAPK<sup>S308</sup> to DAPK. PP2A then dissociated from the C-Raf–DAPK complex and induced profound cancer cell death. Increased pDAPK<sup>S308</sup> modification was also observed in renal cancer tissues, which correlated with poor disease-free survival and poor overall survival in renal cancer patients. Besides mediating the anticancer effect, pDAPK<sup>S308</sup> may serve as a predictive biomarker for Raf inhibitors combination therapy, suggesting an ideal preclinical model that is worthy of clinical translation. <i>Cancer Res; 75(17); 3568–82. ©2015 AACR</i>.</p></div>" @default.
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- W4361238662 date "2023-03-30" @default.
- W4361238662 modified "2023-09-29" @default.
- W4361238662 title "Data from Novel Cancer Therapeutics with Allosteric Modulation of the Mitochondrial C-Raf–DAPK Complex by Raf Inhibitor Combination Therapy" @default.
- W4361238662 doi "https://doi.org/10.1158/0008-5472.c.6506796.v1" @default.
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