Suppression of Extracellular Vesicle VEGF-C-mediated Lymphangiogenesis and Pancreatic Cancer Early Dissemination By a Selective HDAC1/2 Inhibitor.

Abstract

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.

• Authors: Chu-An Wang, Chien-Feng Li, Rho-Chi Huang, Yo-Hua Li, Jing-Ping Liou, Shaw-Jenq Tsai
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 20 Issue 9 Pg. 1550-1560 (09 2021) ISSN: 1538-8514 [Electronic] United States
• PMID: 34210825 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2021 American Association for Cancer Research.

Chemical References

• Histone Deacetylase Inhibitors
• Vascular Endothelial Growth Factor C
• Dual Specificity Phosphatase 2
• Dusp2 protein, mouse
• Histone Deacetylase 1
• Histone Deacetylase 2

Topics

• Animals
• Apoptosis
• Carcinoma, Pancreatic Ductal (drug therapy, metabolism, pathology)
• Cell Proliferation
• Dual Specificity Phosphatase 2 (genetics, metabolism)
• Extracellular Vesicles (metabolism)
• Histone Deacetylase 1 (antagonists & inhibitors)
• Histone Deacetylase 2 (antagonists & inhibitors)
• Histone Deacetylase Inhibitors (pharmacology)
• Humans
• Lymphangiogenesis
• Mice
• Pancreatic Neoplasms (drug therapy, metabolism, pathology)
• Tumor Cells, Cultured
• Vascular Endothelial Growth Factor C (genetics, metabolism)