Suppression of extracellular vesicle VEGF-C-mediated lymphangiogenesis and pancreatic cancer early dissemination by a selective HDAC1/2 inhibitor

Chu An Wang, Chien Feng Li, Rho Chi Huang, Yo Hua Li, Jing Ping Liou, Shaw Jenq Tsai

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摘要

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer characterized by early dissemination and poor drug response. Therefore, it is an unmet medical need to develop new strategies for treatment. As aberrant activation of ERK due to KRAS activating mutation is a driving force for PDAC, a brake system that can terminate ERK signaling represents an ideal druggable target. Herein, we demonstrate that forced expression of dual specificity phosphatase-2 (DUSP2), a specific ERK phosphatase, abrogated tumor formation and loss of Dusp2 facilitated Kras-driven PDAC progression. We report that a selective HDAC1/2 inhibitor (B390) has multifaceted therapeutic potential in PDAC by restoring the expression and function of DUSP2. In vitro study showed that treatment with B390 inhibited growth and migration abilities of PDAC cells, decreased extracellular vesicle-associated VEGF-C expression, and suppressed lymphatic endothelial cell proliferation. In vivo, B390 not only suppressed tumor growth by increasing tumor cell death, it also inhibited lymphangiogenesis and lymphovascular invasion. Taken together, our data demonstrate that B390 was able to alleviate loss of DUSP2-mediated pathologic processes, which provides the proof-of-concept evidence to demonstrate the potential of using selective HDAC1/2 inhibitors in PDAC treatment and suggests reinstating DUSP2 expression may be a strategy to subside PDAC progression.

原文英語
頁(從 - 到)1550-1560
頁數11
期刊Molecular Cancer Therapeutics
20
發行號9
DOIs
出版狀態已發佈 - 九月 2021

ASJC Scopus subject areas

  • 腫瘤科
  • 癌症研究

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