TY - JOUR
T1 - Suppression of extracellular vesicle VEGF-C-mediated lymphangiogenesis and pancreatic cancer early dissemination by a selective HDAC1/2 inhibitor
AU - Wang, Chu An
AU - Li, Chien Feng
AU - Huang, Rho Chi
AU - Li, Yo Hua
AU - Liou, Jing Ping
AU - Tsai, Shaw Jenq
N1 - Funding Information:
C.A. Wang reports grants from Ministry of Science and Technology during the conduct of the study. S.J. Tsai reports grants from Ministry of Science and Technology and grants from National Health Research Institute during the conduct of the study. No disclosures were reported by the other authors.
Funding Information:
We thank Yi-Shang Yeh, Yi-Chen Tang, and Yi-Jou Chung for the technical support in IHC staining and animal experiments. We thank Yen-Yu Lai for bioinformatics analysis. We thank Dr. Cheng-Lin Wu (Department of Pathology, National Cheng Kung Hospital) for the histology consultation. We thank the technical services provided by the “Bioimaging Core Facility of the National Core Facility for Biopharmaceuticals, Ministry of Science and Technology, Taiwan”. We thank Dr. Po-Hsien Huang, Department of Biochemistry and molecular biology, NCKU for the KC transgenic mice. This work was supported by grants from Ministry of Science and Technology (106-2321-B-006 −022-MY3, MOST 108-2321-B-006-006 -) and National Health Research Institute (NHRI-EX105-10516BI, NHRI-EX110-11016BI).
Funding Information:
We thank Taiwan Bioinformatics Institute Core Facility for assistance on using Oncomine (National Core Facility Program for Biotechnology, MOST 108-2319-B-400-001). We thank Yi-Shang Yeh, Yi-Chen Tang, and Yi-Jou Chung for the technical support in IHC staining and animal experiments. We thank Yen-Yu Lai for bioinformatics analysis. We thank Dr. Cheng-Lin Wu (Department of Pathology, National Cheng Kung Hospital) for the histology consultation. We thank the technical services provided by the ?Bioimaging Core Facility of the National Core Facility for Biopharmaceuticals, Ministry of Science and Technology, Taiwan?. We thank Dr. Po-Hsien Huang, Department of Biochemistry and molecular biology, NCKU for the KC transgenic mice. This work was supported by grants from Ministry of Science and Technology (106-2321-B-006-022-MY3, MOST 108-2321-B-006-006 -) and National Health Research Institute (NHRI-EX105-10516BI, NHRIEX110-11016BI).
Publisher Copyright:
© 2021 American Association for Cancer Research
PY - 2021/9
Y1 - 2021/9
N2 - 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.
AB - 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.
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U2 - 10.1158/1535-7163.MCT-20-0963
DO - 10.1158/1535-7163.MCT-20-0963
M3 - Article
C2 - 34210825
AN - SCOPUS:85114233361
SN - 1535-7163
VL - 20
SP - 1550
EP - 1560
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 9
ER -