title: NEK2 mediates ALDH1A1-dependent drug resistance in multiple myeloma.
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.
authors.affiliation: Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, United States.
authors.forename: Ye
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, United States.
authors.forename: Wen
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, United States.
authors.forename: Jiliang
authors.initials: J
authors.lastname: Xia
authors.affiliation: Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, United States.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Gu
authors.affiliation: Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, United States.
authors.forename: Erik
authors.initials: E
authors.lastname: Wendlandt
authors.affiliation: Vanderbilt University, Nashville, Tennessee, United States.
authors.forename: Xin
authors.initials: X
authors.lastname: Zhan
authors.affiliation: Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, United States.
authors.forename: Siegfried
authors.initials: S
authors.lastname: Janz
authors.affiliation: Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, United States.
authors.forename: Guido
authors.initials: G
authors.lastname: Tricot
authors.affiliation: Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, United States.
authors.forename: Fenghuang
authors.initials: F
authors.lastname: Zhan
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000096:biosynthesis*; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005434:Flow Cytometry; D064593:Heterografts; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D009101:Multiple Myeloma / Q000473:pathology*; D000072379:NIMA-Related Kinases; D020411:Oligonucleotide Array Sequence Analysis; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis*; D050697:Retinal Dehydrogenase; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
chemical_list: D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase; C089441:NEK2 protein, human; D000072379:NIMA-Related Kinases; D017346:Protein Serine-Threonine Kinases