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

doi:10.1016/j.canlet.2017.06.020

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.

Authors

Harikrishnan Radhakrishnan¹, Katharina Ilm², Wolfgang Walther², Senji Shirasawa³, Takehiko Sasazuki⁴, Peter T Daniel⁵, Bernhard Gillissen⁵, Ulrike Stein⁶

Affiliations

¹ Translational Oncology of Solid Tumors, Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany; Berlin School of Integrative Oncology, Charité - Universitätsmedizin Berlin, Germany.
² Translational Oncology of Solid Tumors, Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
³ Department of Cell Biology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan.
⁴ Institute for Advanced Study, Kyushu University, Fukuoka, Japan.
⁵ Clinical and Molecular Oncology, Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
⁶ Translational Oncology of Solid Tumors, Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany. Electronic address: ustein@mdc-berlin.de.

PMID: 28649004
DOI: 10.1016/j.canlet.2017.06.020

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