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

Cancer Lett. 2017 Sep 10:403:231-245. doi: 10.1016/j.canlet.2017.06.020. Epub 2017 Jun 23.

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: Bcl-2 family proteins; Fas mediated apoptosis; MACC1; STAT signaling; Solid cancers.

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Apoptosis* / drug effects
  • Caspases / metabolism
  • Colorectal Neoplasms / drug therapy
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / pathology
  • Drug Resistance, Neoplasm
  • Gene Expression Regulation, Neoplastic
  • HCT116 Cells
  • HT29 Cells
  • Humans
  • Janus Kinases / antagonists & inhibitors
  • Janus Kinases / metabolism
  • Myeloid Cell Leukemia Sequence 1 Protein / genetics
  • Myeloid Cell Leukemia Sequence 1 Protein / metabolism*
  • Nitriles
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology
  • Pyrazoles / pharmacology
  • Pyrimidines
  • RNA Interference
  • STAT1 Transcription Factor / metabolism*
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction* / drug effects
  • TNF-Related Apoptosis-Inducing Ligand / pharmacology
  • Time Factors
  • Trans-Activators
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transfection
  • bcl-2 Homologous Antagonist-Killer Protein / genetics
  • bcl-2 Homologous Antagonist-Killer Protein / metabolism
  • bcl-2-Associated X Protein / genetics
  • bcl-2-Associated X Protein / metabolism
  • fas Receptor / metabolism*

Substances

  • Antineoplastic Agents
  • BAK1 protein, human
  • BAX protein, human
  • FAS protein, human
  • MACC1 protein, human
  • MCL1 protein, human
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Nitriles
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyrimidines
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Trans-Activators
  • Transcription Factors
  • bcl-2 Homologous Antagonist-Killer Protein
  • bcl-2-Associated X Protein
  • fas Receptor
  • ruxolitinib
  • Janus Kinases
  • Caspases