NEK2 mediates ALDH1A1-dependent drug resistance in multiple myeloma

Ye Yang; Wen Zhou; Jiliang Xia; Zhimin Gu; Erik Wendlandt; Xin Zhan; Siegfried Janz; Guido Tricot; Fenghuang Zhan

doi:10.18632/oncotarget.2388

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NEK2 mediates ALDH1A1-dependent drug resistance in multiple myeloma

Journal article

Open access

Peer reviewed

NEK2 mediates ALDH1A1-dependent drug resistance in multiple myeloma

Ye Yang, Wen Zhou, Jiliang Xia, Zhimin Gu, Erik Wendlandt, Xin Zhan, Siegfried Janz, Guido Tricot and Fenghuang Zhan

Oncotarget, Vol.5(23), pp.11986-11997

12/15/2014

DOI: 10.18632/oncotarget.2388

PMCID: PMC4322982

PMID: 25230277

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https://doi.org/10.18632/oncotarget.2388View

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Abstract

We reported previously that increased expression of aldehyde dehydrogenase 1 (ALDH1) in multiple myeloma (MM) is a marker of tumor-initiating cells (TICs) that is further associated with chromosomal instability (CIN). Here we demonstrate that member A1 of the ALDH1 family of proteins, ALDH1A1, is most abundantly expressed in myeloma. Enforced expression of ALDH1A1 in myeloma cells led to increased clonogenicity, tumor formation in mice, and resistance to myeloma drugs in vitro and in vivo. The mechanism underlying these phenotypes included the ALDH1A1-dependent activation of drug-efflux pump, ABCB1, and survival proteins, AKT and BCL2. Over expression of ALDH1A1 in myeloma cells led to increased mRNA and protein levels of NIMA-related kinase 2 (NEK2), whereas shRNA-mediated knock down of NEK2 decreased drug efflux pump activity and drug resistance. The activation of NEK2 in myeloma cells relied on the ALDH1A1-dependent generation of the retinoid X receptor α (RXRα) ligand, 9-cis retinoic acid (9CRA) - not the retinoic acid receptor α (RARα) ligand, all-trans retinoic acid (ATRA). These findings implicate the ALDH1A1-RXRα-NEK2 pathway in drug resistance and disease relapse in myeloma and suggest that specific inhibitors of ALDH1A1 are worthy of consideration for clinical development of new approaches to overcome drug resistance in myeloma.

Flow Cytometry

Up-Regulation

Oligonucleotide Array Sequence Analysis

Humans

Aldehyde Dehydrogenase - biosynthesis

Reverse Transcriptase Polymerase Chain Reaction

Blotting, Western

Protein-Serine-Threonine Kinases - biosynthesis

Multiple Myeloma - pathology

Animals

Heterografts

Cell Line, Tumor

Mice, Inbred NOD

Mice

Apoptosis - physiology

Drug Resistance, Neoplasm - physiology

NIMA-Related Kinases

Details

Title: Subtitle: NEK2 mediates ALDH1A1-dependent drug resistance in multiple myeloma
Creators: Ye Yang - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, United States
Wen Zhou - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, United States
Jiliang Xia - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, United States
Zhimin Gu - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, United States
Erik Wendlandt - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, United States
Xin Zhan - Vanderbilt University
Siegfried Janz - Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, United States
Guido Tricot - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, United States
Fenghuang Zhan - Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, United States
Resource Type: Journal article
Publication Details: Oncotarget, Vol.5(23), pp.11986-11997
DOI: 10.18632/oncotarget.2388
PMID: 25230277
PMCID: PMC4322982
NLM abbreviation: Oncotarget
ISSN: 1949-2553
eISSN: 1949-2553
Grant note: R01 CA152105 / NCI NIH HHS R01 CA151354 / NCI NIH HHS T32 HL007344 / NHLBI NIH HHS R01CA152105 / NCI NIH HHS R01CA151354 / NCI NIH HHS T32 HL007734 / NHLBI NIH HHS T32 HL07734 / NHLBI NIH HHS P30 CA086862 / NCI NIH HHS
Language: English
Date published: 12/15/2014
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Pathology; Surgery; Internal Medicine
Record Identifier: 9984083287102771

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