title: Induction of chemoresistance by all-trans retinoic acid via a noncanonical signaling in multiple myeloma cells.
abstract: Despite the successful application of all-trans retinoic acid (ATRA) in multiple myeloma treatment, ATRA-induced chemoresistance in the myeloma patients is very common in clinic. In this study, we evaluated the effect of ATRA on the expression of apurinic endonuclease/redox factor-1 (Ape/Ref-1) in the U266 and RPMI-8226 myeloma cells to explore the chemoresistance mechanism involved. ATRA treatment induced upregulation of Ape/Ref-1 via a noncanonical signaling pathway, leading to enhanced pro-survival activity counteracting melphalan (an alkylating agent). ATRA rapidly activated p38-MSK (mitogen- and stress activated protein kinase) cascade to phosphorylate cAMP response element-binding protein (CREB). Phosphorylated CREB was recruited to the Ape/Ref-1 promoter to evoke the gene expression. The stimulation of ATRA on Ape/Ref-1 expression was attenuated by either p38-MSK inhibitors or overexpression of dominant-negative MSK1 mutants. Moreover, ATRA-mediated Ape/Ref-1 upregulation was correlated with histone modification and activation of CBP/p300, an important cofactors for CREB transcriptional activity. C646, a competitive CBP/p300 inhibitor, abolished the upregulation of Ape/Ref-1 induced by ATRA. Intriguingly, CBP rather than p300 played a dominant role in the expression of Ape/Ref-1. Hence, our study suggests the existence of a noncanonical mechanism involving p38-MSK-CREB cascade and CBP induction to mediate ATRA-induced Ape/Ref-1 expression and acquired chemoresistance in myeloma cells.
authors.affiliation: Department of Lymphoma and Myeloma, Division of Cancer Medicine, Center for Cancer Immunology Research, the University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Biology, College of Chemistry and Life Sciences, Zhejiang Normal University, Jinhua, Zhejiang, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Li
authors.affiliation: Department of Biology, College of Chemistry and Life Sciences, Zhejiang Normal University, Jinhua, Zhejiang, China.
authors.forename: Kesheng
authors.initials: K
authors.lastname: Jiang
authors.affiliation: Department of Biology, College of Chemistry and Life Sciences, Zhejiang Normal University, Jinhua, Zhejiang, China.
authors.forename: Qiaoli
authors.initials: Q
authors.lastname: Huang
authors.affiliation: Department of Urology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Yicheng
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Medical Function, Medical School of Yangtze University, Jingzhou, Hubei, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Qian
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008558:Melphalan / Q000494:pharmacology / Q000627:therapeutic use; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology / Q000627:therapeutic use*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D050880:p300-CBP Transcription Factors / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D008558:Melphalan; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D014212:Tretinoin; D050880:p300-CBP Transcription Factors; D048051:p38 Mitogen-Activated Protein Kinases; D000099224:p300-CBP-Associated Factor; C116919:mitogen and stress-activated protein kinase 1; C085108:APEX1 protein, human