Guan Chen, MD, PhD
1985, Sun Yat-Sen University, MS
1990, University of Heidelberg, Germany, PhD
- p38gamma MAPK, Cancer Signaling, Ras Oncogenesis, Nuclear Receptors, Targeted Cancer Therapy
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.
Isoform-specific and cell/tissue-dependent effects of p38 MAPKs in regulating inflammation and inflammation-associated oncogenesis.
(Qin JZ, Xin H, Qi XM, Chen G.) Front Biosci (Landmark Ed). 2022 Jan 18;27(1):31 PMID: 35090336 SCOPUS ID: 2-s2.0-85124820704 01/30/2022
p38γ MAPK Is Essential for Aerobic Glycolysis and Pancreatic Tumorigenesis.
(Wang F, Qi XM, Wertz R, Mortensen M, Hagen C, Evans J, Sheinin Y, James M, Liu P, Tsai S, Thomas J, Mackinnon A, Dwinell M, Myers CR, Bartrons Bach R, Fu L, Chen G.) Cancer Res. 2020 Aug 15;80(16):3251-3264 PMID: 32580961 PMCID: PMC9358694 SCOPUS ID: 2-s2.0-85089787021 06/26/2020
p38gamma MAPK Is Essential for Aerobic Glycolysis and Pancreatic Tumorigenesis
(Fang Wang, Xiao-Mei Qi, Ryan Wertz, Matthew Mortensen, Catherine Hagen, John Evans, Yuri Sheinin, Michael James, Pengyuan Liu, Susan Tsai, James Thomas, Alexander Mackinnon, Michael Dwinell, Charles R Myers, Ramon Bartrons, Liwu Fu, Guan Chen.) Cancer Research. Wang F, Qi XM, Wertz R, et al. p38gamma MAPK is essential for aerobic glycolysis and pancreatic tumorigenesis [published online ahead of print, 2020 Jun 24]. Cancer Res. 2020;canres.3281.2019. doi:10.1158/0008-5472.CAN-19-3281 06/24/2020
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 PMID: 30109176 PMCID: PMC6089844 SCOPUS ID: 2-s2.0-85048878016 08/16/2018
Editorial Preface for Targeted Cancer Therapy.
(Chen G, Li W.) Acta Pharm Sin B. 2018 Jul;8(4):501-502 PMID: 30109174 PMCID: PMC6090083 08/16/2018
Editorial Preface for Targeted Cancer Therapy
(Chen G, Li W.) Acta Pharmaceutica Sinica B. July 2018;8(4):501-502 SCOPUS ID: 2-s2.0-85050349538 07/01/2018
The K-Ras effector p38γ MAPK confers intrinsic resistance to tyrosine kinase inhibitors by stimulating EGFR transcription and EGFR dephosphorylation.
(Yin N, Lepp A, Ji Y, Mortensen M, Hou S, Qi XM, Myers CR, Chen G.) J Biol Chem. 2017 Sep 08;292(36):15070-15079 PMID: 28739874 PMCID: PMC5592682 SCOPUS ID: 2-s2.0-85029228747 07/26/2017
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 PMID: 25961922 SCOPUS ID: 2-s2.0-84959509513 05/12/2015
p38γ MAPK Is a Therapeutic Target for Triple-Negative Breast Cancer by Stimulation of Cancer Stem-Like Cell Expansion.
(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 PMID: 26077647 PMCID: PMC4792188 SCOPUS ID: 2-s2.0-84940467357 06/17/2015
Tyrosine dephosphorylation enhances the therapeutic target activity of epidermal growth factor receptor (EGFR) by disrupting its interaction with estrogen receptor (ER).
(Ma S, Yin N, Qi X, Pfister SL, Zhang MJ, Ma R, Chen G.) Oncotarget. 2015 May 30;6(15):13320-33 PMID: 26079946 PMCID: PMC4537017 SCOPUS ID: 2-s2.0-84931073824 06/17/2015
Identification of a ternary protein-complex as a therapeutic target for K-Ras-dependent colon cancer.
(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 PMID: 24962213 PMCID: PMC4147322 SCOPUS ID: 2-s2.0-84905098265 06/26/2014
Protein-tyrosine phosphatase H1 increases breast cancer sensitivity to antiestrogens by dephosphorylating estrogen receptor at Tyr537.
(Suresh PS, Ma S, Migliaccio A, Chen G.) Mol Cancer Ther. 2014 Jan;13(1):230-8 PMID: 24227889 SCOPUS ID: 2-s2.0-84892585177 11/15/2013