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MACC1 regulates Fas mediated apoptosis through STAT1/3 - Mcl-1 signaling in solid cancers

Item Type:Article
Title:MACC1 regulates Fas mediated apoptosis through STAT1/3 - Mcl-1 signaling in solid cancers
Creators Name:Radhakrishnan, H. and Ilm, K. and Walther, W. and Shirasawa, S. and Sasazuki, T. and Daniel, P.T. and Gillissen, B. and Stein, U.
Abstract:MACC1 was identified as a novel player in cancer progression and metastasis, but its role in death receptor-mediated apoptosis is still unexplored. We show that MACC1 knockdown sensitizes cancer cells to death receptor-mediated apoptosis. For the first time, we provide evidence for STAT signaling as a MACC1 target. MACC1 knockdown drastically reduced STAT1/3 activating phosphorylation, thereby regulating the expression of its apoptosis targets Mcl-1 and Fas. STAT signaling inhibition by the JAK1/2 inhibitor ruxolitinib mimicked MACC1 knockdown-mediated molecular signatures and apoptosis sensitization to Fas activation. Despite the increased Fas expression, the reduced Mcl-1 expression was instrumental in apoptosis sensitization. This reduced Mcl-1-mediated apoptosis sensitization was Bax and Bak dependent. MACC1 knockdown also increased TRAIL-induced apoptosis. MACC1 overexpression enhanced STAT1/3 phosphorylation and increased Mcl-1 expression, which was abrogated by ruxolitinib. The central role of Mcl-1 was strengthened by the resistance of Mcl-1 overexpressing cells to apoptosis induction. The clinical relevance of Mcl-1 regulation by MACC1 was supported by their positive expression correlation in patient-derived tumors. Altogether, we reveal a novel death receptor-mediated apoptosis regulatory mechanism by MACC1 in solid cancers through modulation of the STAT1/3-Mcl-1 axis.
Keywords:Solid Cancers, MACC1, STAT Signaling, Fas Mediated Apoptosis, Bcl-2 Family Proteins
Source:Cancer Letters
Page Range:231-245
Date:10 September 2017
Official Publication:https://doi.org/10.1016/j.canlet.2017.06.020
PubMed:View item in PubMed

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