Oncotarget

Research Papers:

RSK-mediated down-regulation of PDCD4 is required for proliferation, survival, and migration in a model of triple-negative breast cancer

Rafael Cuesta _ and Marina K. Holz

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Oncotarget. 2016; 7:27567-27583. https://doi.org/10.18632/oncotarget.8375

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Abstract

Rafael Cuesta1 and Marina K. Holz1,2,3

1Department of Biology, Stern College for Women of Yeshiva University, New York, New York 10016, USA

2Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461, USA

3Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA

Correspondence to:

Rafael Cuesta, email: [email protected]

Marina K. Holz, email: [email protected]

Keywords: RSKs, PDCD4, translational control, MAPK upregulation, TNBC biology

Received: December 03, 2015     Accepted: March 14, 2016     Published: March 25, 2016

ABSTRACT

The p90 ribosomal S6 kinase (RSK) is a family of MAPK-activated serine/threonine kinases (RSK1-4) whose expression and/or activity are deregulated in several cancers, including breast cancer. Up-regulation of RSKs promotes cellular processes that drive tumorigenesis in Triple Negative Breast Cancer (TNBC) cells. Although RSKs regulate protein synthesis in certain cell types, the role of RSK-mediated translational control in oncogenic progression has yet to be evaluated. We demonstrate that proliferation and migration of TNBC MDA-MB-231 cells, unlike ER/PR-positive MCF7 cells, rely on RSK activity. We show that RSKs regulate the activities of the translation initiation factor eIF4B and the translational repressor PDCD4 in TNBC cells with up-regulated MAPK pathway, but not in breast cancer cells with hyperactivated PI3K/Akt/mTORC1 pathway. These results identify PDCD4 as a novel RSK substrate. We demonstrate that RSK-mediated phosphorylation of PDCD4 at S76 promotes PDCD4 degradation. Low PDCD4 levels reduce PDCD4 inhibitory effect on the translation initiation factor eIF4A, which increases translation of “eIF4A sensitive” mRNAs encoding factors involved in cell cycle progression, survival, and migration. Consequently, low levels of PDCD4 favor proliferation and migration of MDA-MB-231 cells. These results support the therapeutic use of RSK inhibitors for treatment of TNBC with deregulated MAPK/RSK pathway.


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