Elucidation of the mechanism of drug resistance in cancer stem cells regulated by actin cytoskeleton dynamics and therapeutic strategies based on this mechanism

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K07131
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Fujita Health University
• Principal Investigator: Nobusue Hiroyuki 藤田医科大学, 腫瘍医学研究センター, 講師 (90525685)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: アクチン細胞骨格 / がん幹細胞 / 薬剤耐性 / 骨肉腫 / MKL1

Outline of Final Research Achievements

We previously established osteosarcoma-initiating (OSi) cells by overexpression of c-Myc in bone marrow stromal cells derived from Ink4a/Arf (-/-) mice. Osi cells are composed of two distinct clones: chemosensitive AX cells and chemoresistant AO cells. We found that AO cells survived after the doxorubicin treatment exhibited excessive actin polymerization and nuclear translocation of and transcriptional activation by MKL1 (megakaryoblastic leukemia 1) which is associated with actin cytoskeleton dynamics. In addition, depletion of MKL1 enhanced the sensitivity of AO cells to doxorubicin whereas, conversely, overexpression of MKL1 attenuated that of AX cells to doxorubicin. Furthermore, we found that inhibition of actin polymerization potentiated the antitumor activity of doxorubicin in human OS cell lines through inactivation of MKL1.These finding suggest thus that MKL1 acts as a key molecule in regulating the chemoresistance of OS cells.

Free Research Field

腫瘍生物学

Academic Significance and Societal Importance of the Research Achievements

本研究成果は、細胞骨格構成要素であるアクチンの動態を分子標的として制御することで、転写制御シグナルを変化させ、がん幹細胞の薬剤耐性を阻害し腫瘍抑制するという新規治療法の開発に繋がるものであり、学術的に新しい概念を生み出すだけでなく、社会的意義も極めて大きいと考える。