Analysis of the mechanism of PRMT5-mediated pancreatic cancer stem cells maintenance, and development of therapeutic strategy targeting pancreatic cancer stem cells by PRMT5 inhibition

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K09044
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Nippon Medical School
• Principal Investigator: Abe Yoshinori 日本医科大学, 研究部共同研究施設, 講師 (00386153)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: PRMT5 / 膵癌 / アルギニンメチル基転移酵素

Outline of Final Research Achievements

We conducted RNA-seq analysis and found that PRMT5 upregulated gene expression involved in integrin signaling and RAS-ERK signaling pathways in pancreatic cancer cells. Additionally, we observed that inhibition of PRMT5 altered the splicing variants of several genes. We evaluated the effective dose of PRMT5 inhibitors developed by GlaxoSmithKline and determined the optimal dose through both in vitro and in vivo experiments. Our findings indicated that epithelial pancreatic cancer cells are more sensitive to PRMT5 inhibitors than mesenchymal cancer cells. Furthermore, the sensitivity of pancreatic cancer cells to PRMT5 inhibitors was found to correlate with PRMT5 expression levels. Based on RNA-seq results, we also found that the combination of a MEK inhibitor (Trametinib) and a PRMT5 inhibitor exhibited a high antitumor effect on these pancreatic cancer cells.

Free Research Field

分子生物学

Academic Significance and Societal Importance of the Research Achievements

PRMT5は膵癌細胞において、インテグリンを介したシグナル伝達制御やRAS-ERKシグナル伝達制御に関わる遺伝子群を発現制御することが分かった。さらに発現変動する遺伝子群の中には、スプライシングバリアントの発現が変化する遺伝子も複数同定された。同時に、GlaxoSmithKlineが開発中のPRMT5阻害剤は、PRMT5の発現量で感受性が規定されることを見出した。このような膵癌細胞に対して、RNA-Seqの結果をもとに、MEK阻害剤とPRMT5阻害剤の併用が高い抗腫瘍効果を発揮することが分かった。