
Guan Chen, MD, PhD
Professor
Contact Information
General Interests
Education
1985, Sun Yat-Sen University, MS
1990, University of Heidelberg, Germany, PhD
Research Experience
- p38gamma MAPK, Cancer Signaling, Ras Oncogenesis, Nuclear Receptors, Targeted Cancer Therapy
Research Interests
Cancer remains a life-threatening disease and there is an urgent need to identify novel molecular targets for therapeutic intervention. Our lab focuses on investigating oncogenic activity of p38gamma in colon, breast and pancreatic cancers. In colon cancer, p38gamma is required for K-Ras induced transformation and for K-Ras-dependent malignant growth through mechanisms involving collaboration with its phosphatase PTPH1, stimulating c-Jun/AP-1-dependent MMP9 transcription, and/or phosphorylating and activating Hsp90. p38gamma activation also causes increased EGFR transcription via -c-Jun and decreased EGFR phosphorylation via PTPH1, resulting in accumulation of non-phosphorylated EGFR and resistance to tyrosine kinase inhibitors. In breast cancer, p38gamma-overexpression alone induces malignant transformation in human mammary epithelial cells leading to a phenotype resembling triple-negative breast cancer (TNBC). p38gamma also promotes TNBC growth and metastasis by stimulating cancer-like stem cell (CSC) expansion. Moreover, p38gamma phosphorylates estrogen receptor alpha (ER) and DNA Topoisomerase II alpha, likely further contributing to TNBC phenotype. Importantly, the p38gamma pharmacological inhibitor pirfenidone (PFD) suppresses xenograft growth of K-Ras-mutated colon cancer and TNBC in nude mice. These results together indicate that p38gamma is an important therapeutic target in K-Ras mutated colon cancer and in TNBC.
We recently further investigated roles of p38gamma in tumorigenesis in genetic mouse models of colon and breast cancers. Conditional knockout (KO) of p38gamma from intestinal epithelial cells suppresses AOM/DSS-induced colon cancer and inhibits beta-catenin/Wnt pathways and systemic application of PFD shows similar effects in wild-type, but not in p38gamma KO, mice. Further, conditional p38gamma KO from mammary epithelial cells inhibits breast cancer development in a PyMT mouse model. Currently, we are studying effects of p38gamma KO on mouse pancreatic cancer development in a KPC mouse model. Because p38gamma activates several key molecules in glycolysis, we will in future exploit if p38gamma is a master activator of aerobic glycolysis, a hallmark of cancer, and thereby promotes cancer development and growth by activating metabolic reprogramming.
Visit Dr. Chen's Faculty Collaborative Database profile for additional information.
Publications
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Targeting an oncogenic kinase/phosphatase signaling network for cancer therapy.
(Qi XM, Wang F, Mortensen M, Wertz R, Chen G.) Acta Pharm Sin B. 2018 Jul;8(4):511-517.
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(Yin N, Lepp A, Ji Y, Mortensen M, Hou S, Qi XM, Myers CR, Chen G.) J Biol Chem. 2017 09 08;292(36):15070-15079.
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p38γ MAPK is required for inflammation-associated colon tumorigenesis.
(Yin N, Qi X, Tsai S, Lu Y, Basir Z, Oshima K, Thomas JP, Myers CR, Stoner G, Chen G.) Oncogene. 2016 Feb 25;35(8):1039-48.
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(Qi X, Yin N, Ma S, Lepp A, Tang J, Jing W, Johnson B, Dwinell MB, Chitambar CR, Chen G.) Stem Cells. 2015 Sep;33(9):2738-47.
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(Ma S, Yin N, Qi X, Pfister SL, Zhang MJ, Ma R, Chen G.) Oncotarget. 2015 May 30;6(15):13320-33.
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(Qi X, Xie C, Hou S, Li G, Yin N, Dong L, Lepp A, Chesnik MA, Mirza SP, Szabo A, Tsai S, Basir Z, Wu S, Chen G.) Oncotarget. 2014 Jun 30;5(12):4269-82.
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(Suresh PS, Ma S, Migliaccio A, Chen G.) Mol Cancer Ther. 2014 Jan;13(1):230-8.
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(Hou S, Suresh PS, Qi X, Lepp A, Mirza SP, Chen G.) J Biol Chem. 2012 Aug 10;287(33):27895-905.
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MK2 Regulates Ras Oncogenesis through Stimulating ROS Production.
(Kobayashi Y, Qi X, Chen G.) Genes Cancer. 2012 Jul;3(7-8):521-30.
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(Qi X, Zhi H, Lepp A, Wang P, Huang J, Basir Z, Chitambar CR, Myers CR, Chen G.) J Biol Chem. 2012 Apr 27;287(18):14681-91.
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(Qi X, Hou S, Lepp A, Li R, Basir Z, Lou Z, Chen G.) J Biol Chem. 2011 Oct 14;286(41):35883-90.
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Editorial Preface for Targeted Cancer Therapy
(Chen G, Li W.) Acta Pharmaceutica Sinica B. July 2018;8(4):501-502.