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

Harikrishnan Radhakrishnan, Katharina Ilm, Wolfgang Walther, Senji Shirasawa, Takehiko Sasazuki, Peter T. Daniel, Bernhard Gillissen, Ulrike Stein

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)231-245
Number of pages15
JournalCancer Letters
Volume403
DOIs
Publication statusPublished - Sep 10 2017

    Fingerprint

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Radhakrishnan, H., Ilm, K., Walther, W., Shirasawa, S., Sasazuki, T., Daniel, P. T., ... Stein, U. (2017). MACC1 regulates Fas mediated apoptosis through STAT1/3 – Mcl-1 signaling in solid cancers. Cancer Letters, 403, 231-245. https://doi.org/10.1016/j.canlet.2017.06.020