title: RSK2(Ser227) at N-terminal kinase domain is a potential therapeutic target for multiple myeloma.
abstract: Multiple myeloma is an entity of cytogenetically and genetically heterogenous plasma cell neoplasms. Despite recent improvement in the treatment outcome of multiple myeloma by novel molecular-targeted chemotherapeutics, multiple myeloma remains incurable. The identification of a therapeutic target molecule in which various signaling for cell-survival converge is a core component for the development of new therapeutic strategies against multiple myeloma. RSK2 is an essential mediator of the ERK1/2 signaling pathway for cell survival and proliferation. In this study, we discovered that RSK2(Ser227), which is located at the N-terminal kinase domain and is one site responsible for substrate phosphorylation, is activated through phosphorylation regardless of the type of cytogenetic abnormalities or upstream molecular signaling in all 12 multiple myeloma-derived cell lines examined and 6 of 9 patient-derived CD138-positive primary myeloma cells. The chemical inhibition of RSK2(Ser227) by BI-D1870 or gene knockdown of RSK2 inhibits myeloma cell proliferation through apoptosis induction, and this anti-myeloma effect was accompanied by downregulation of c-MYC, cyclin D, p21(WAF1/CIP1), and MCL1. RSK2(Ser227) inhibition resulting from BI-D1870 treatment restored lenalidomide-induced direct cytotoxicity of myeloma cells from interleukin-6-mediated cell protection, showed no cross-resistance to bortezomib, and exerted additive/synergistic antiproliferative effects in conjunction with the mTOR, histone deacetylase, and BH3-mimicking BCL2/BCLX(L) inhibitors. These results suggest that RSK2(Ser227) is a potential therapeutic target not only for newly diagnosed but also for patients with later phase multiple myeloma who are resistant or refractory to currently available anti-myeloma therapies.
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Shimura
authors.forename: Junya
authors.initials: J
authors.lastname: Kuroda
authors.forename: Masaki
authors.initials: M
authors.lastname: Ri
authors.forename: Hisao
authors.initials: H
authors.lastname: Nagoshi
authors.forename: Mio
authors.initials: M
authors.lastname: Yamamoto-Sugitani
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Miki
authors.initials: M
authors.lastname: Kiyota
authors.forename: Ryuko
authors.initials: R
authors.lastname: Nakayama
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Mizutani
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Chinen
authors.forename: Natsumi
authors.initials: N
authors.lastname: Sakamoto
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Shigeo
authors.initials: S
authors.lastname: Horiike
authors.forename: Yukimasa
authors.initials: Y
authors.lastname: Shiotsu
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Iida
authors.forename: Masafumi
authors.initials: M
authors.lastname: Taniwaki
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D048708:Cell Growth Processes / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques; D006801:Humans; D058990:Molecular Targeted Therapy; D009101:Multiple Myeloma / Q000201:enzymology* / Q000235:genetics / Q000628:therapy*; D010766:Phosphorylation; D054730:Protein Interaction Domains and Motifs; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011621:Pteridines / Q000494:pharmacology; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection
chemical_list: C516541:BI D1870; D047428:Protein Kinase Inhibitors; D011621:Pteridines; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3