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Cited by 37PI3K/AKT/mTOR signaling in cancerProtein Kinase Regulation and GTPase SignalingCancer Mechanisms and Therapy

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

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Cuesta, Rafael, Holz, Marina K.·2016·Oncotarget
DOI 10.18632/oncotarget.8375PMC PMC5053672
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Abstract

// Rafael Cuesta 1 and Marina K. Holz 1, 2, 3 1 Department of Biology, Stern College for Women of Yeshiva University, New York, New York 10016, USA 2 Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461, USA 3 Albert Einstein Cancer Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA Correspondence to: Rafael Cuesta, email: Rafael.Cuesta@yu.edu Marina K. Holz, email: mholz@yu.edu 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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Authors
Cuesta, R., & Holz, M. K.
Affiliations
  • Yeshiva University (US)
  • Albert Einstein College of Medicine (US)
ORCID
Venue
Oncotarget
Publisher
Impact Journals, LLC
Published
2016-03-25
Volume
7
Issue
19
Pages
27567-27583
ISSN
1949-2553 (ISSN-L)
DOI
10.18632/oncotarget.8375
PMC
PMC5053672
OpenAlex
W2302692370
Cited by
37
References
56
Citations by year
2026: 3 · 2025: 3 · 2024: 2 · 2023: 7 · 2022: 3 · 2021: 2 · 2020: 3 · 2019: 6 · 2018: 5 · 2017: 2 · 2015: 1
FWCI
2.25
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Oncotarget (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
National Cancer Institute (R15CA151112)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Cancer Mechanisms and Therapy
Keywords
p90 ribosomal S6 kinase, RSK, PDCD4, triple-negative breast cancer, translational regulation, eIF4B, eIF4A, MAPK signaling, protein degradation, cell proliferation, cell migration, cell survival, RSK inhibitors, MDA-MB-231 cells, PI3K/Akt/mTORC1 pathway
MeSH terms
Cell Movement, Humans, Transfection, Signal Transduction, Down-Regulation, RNA-Binding Proteins, Apoptosis, Ribosomal Protein S6 Kinases, 90-kDa, Cell Line, Tumor, Cell Proliferation, Apoptosis Regulatory Proteins, HEK293 Cells, MCF-7 Cells, Triple Negative Breast Neoplasms

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