Oncotarget

Research Papers:

Survivin antagonizes chemotherapy-induced cell death of colorectal cancer cells

Anke Rauch, Annemarie Carlstedt, Claudia Emmerich, Al-Hassan M. Mustafa, Anja Göder, Shirley K. Knauer, Michael Linnebacher, Thorsten Heinzel and Oliver H. Krämer _

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Oncotarget. 2018; 9:27835-27850. https://doi.org/10.18632/oncotarget.25600

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Abstract

Anke Rauch1, Annemarie Carlstedt1,2, Claudia Emmerich1, Al-Hassan M. Mustafa3, Anja Göder3, Shirley K. Knauer4, Michael Linnebacher5, Thorsten Heinzel1,* and Oliver H. Krämer3,*

1Center for Molecular Biomedicine, Institute of Biochemistry and Biophysics, Department of Biochemistry, Friedrich Schiller University Jena, 07745 Jena, Germany

2Leibniz Institute on Aging, Fritz Lipmann Institute, 07745 Jena, Germany

3Department of Toxicology, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany

4Department of Molecular Biology, Centre for Medical Biotechnology (ZMB), University of Duisburg-Essen, 45141 Essen, Germany

5Department of General Surgery, Molecular Oncology and Immunotherapy, University of Rostock, 18057 Rostock, Germany

*Equal senior author contribution

Correspondence to:

Oliver H. Krämer, email: okraemer@uni-mainz.de

Thorsten Heinzel, email: t.heinzel@uni-jena.de

Keywords: ATR; irinotecan; oxaliplatin; p53; survivin

Received: April 30, 2018     Accepted: May 08, 2018     Published: June 12, 2018

ABSTRACT

Irinotecan (CPT-11) and oxaliplatin (L-OHP) are among the most frequently used drugs against colorectal tumors. Therefore, it is important to define the molecular mechanisms that these agents modulate in colon cancer cells. Here we demonstrate that CPT-11 stalls such cells in the G2/M phase of the cell cycle, induces an accumulation of the tumor suppressor p53, the replicative stress/DNA damage marker γH2AX, phosphorylation of the checkpoint kinases ATM and ATR, and an ATR-dependent accumulation of the pro-survival molecule survivin. L-OHP reduces the number of cells in S-phase, stalls cell cycle progression, transiently triggers an accumulation of low levels of γH2AX and phosphorylated checkpoint kinases, and L-OHP suppresses survivin expression at the mRNA and protein levels. Compared to CPT-11, L-OHP is a stronger inducer of caspases and p53-dependent apoptosis. Overexpression and RNAi against survivin reveal that this factor critically antagonizes caspase-dependent apoptosis in cells treated with CPT-11 and L-OHP. We additionally show that L-OHP suppresses survivin through p53 and its downstream target p21, which stalls cell cycle progression as a cyclin-dependent kinase inhibitor (CDKi). These data shed new light on the regulation of survivin by two clinically significant drugs and its biological and predictive relevance in drug-exposed cancer cells.


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