Soluble cytokines derived from bone marrow-derived mesenchymal stem cells activated androgen receptor phosphorylation in human prostate cancer cells through ERK/MAP signaling pathways

2019 Fiscal Year Final Research Report

• Project/Area Number: 16K11014
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Urology
• Research Institution: Oita University
• Principal Investigator: NOMURA TAKEO 大分大学, 医学部, 客員研究員 (40347034)
• Co-Investigator(Kenkyū-buntansha): 三股 浩光 大分大学, 医学部, 教授 (60219714)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Keywords: 前立腺癌 / 骨転移 / 骨髄由来間葉系幹細胞

Outline of Final Research Achievements

Accumulated evidence suggests stromal-epithelial interactions are critical to the progression of prostate cancer. In this study, we examined AR phosphorylation in LNCaP cells co-cultured with the conditioned medium (CM) from human bone marrow-derived mesenchymal stem cells (BMSCs). LNCaP cells proliferated significantly in BMSCs co-culture, and their invasion and migration abilities increased 2.13 times and 2.75 times, respectively. AR-Akt phosphorylation was enhanced in LNCaP cells under co-culture, but ERK phosphorylation was unchanged. The expression of Snail and Slug was also enhanced in co-culture, and Snail was translocated into the nucleus. The Akt inhibitor suppressed proliferation, invasion and migration of LNCaP cells, and suppressed AR phosphorylation. From the above results, it was suggested that the cell proliferation enhancement of LNCaP cells produced by co-culture with BMSCs is controlled by the Akt-AR signal transduction system.

Free Research Field

前立腺癌治療

Academic Significance and Societal Importance of the Research Achievements

前立腺癌骨転移モデルでは前立腺癌細胞と骨髄由来間葉系幹細胞（Bone marrow-derived mesenchymal stem cells; BMSCs）の相互作用により癌細胞の増殖・浸潤・遊走能が亢進することが証明された。分子学的解析によりBMSCsが産生・分泌するサイトカインが癌細胞細胞を刺激し、PI3K/AktおよびMAPKシグナル伝達系を介したAR活性化が悪性形質獲得に寄与することが判明した。
今後中和抗体を使用したサイトカイン中和療法やPI3K/AktおよびMAPKシグナル伝達系阻害剤を使用した骨転移巣治療の可能性に期待がもたれる。