Zhang (Lin) Lab

Zhang lab

The Zhang lab studies the molecular mechanisms of apoptosis induced by anti-cancer agents. Common epithelial malignancies, including cancers of breast, colon and lung, are often resistant to standard treatments such as chemotherapy and irradiation. We are investigating how apoptosis regulators, including PUMA, Bax and SMAC/Diablo, mediate apoptosis induced by anticancer agents, and whether deregulation of these proteins contributes to acquired resistance to anticancer agents. We identified PUMA as a BH3-only Bcl-2 family protein that plays an essential role in DNA damage-induced and p53-dependent apoptosis. We also found that the proapoptotic Bcl-2 family protein BAX and the mitochondrial apoptogenic protein SMAC/Diablo mediate apoptosis induced by NSAIDs (non-steroidal anti-inflammatory drugs), which have been used for chemoprevention of colon cancer. Efforts are currently undertaken to restore apoptosis regulation in human cancer cells by modulating these proteins. The long-term goal of our research is to develop improved strategies and novel agents for chemotherapy and chemoprevention of human cancer.


Dongshi Chen, PhD
Postdoctoral Associate


Kyle Knickelbein
Graduate Student Researcher


Lin Zhang, PhD
Professor

Kyle Knickelbein

Li, L., Knickelbein, K., Zhang, L., Wang, J., Obrinske, M., Ma, G.Z., Zhang, L.M., Bitterman, L. and Du, W. (2015) Amphiphilic sugar poly (orthoesters) as ph-responsive nanoscopic assemblies for acidity-enhanced drug delivery and cell killing. Chemical Communications 51 :13078-13081. PMID: 26096366
 
Knickelbein K, Zhang L. Mutant KRAS as a critical determinant of the therapeutic response of colorectal cancer. Genes Dis. 2015 Mar;2(1):4-12. PMID: 25815366 [PubMed] PMCID:  PMC4372129
 

Fu L, Li L, Wang J, Knickelbein K, Zhang L, Milligan I, Xu Y, O'Hara K, Bitterman L, Du W. Synthesis of clickable amphiphilic polysaccharides as nanoscopic assemblies. Chem Commun (Camb). 2014 Oct 28;50(84):12742-5. doi: 10.1039/c4cc06343k. PubMed PMID: 25204678.

Sun J, Knickelbein K, He K, Chen D, Dudgeon C, Shu Y, Yu J, Zhang L. Aurora kinase inhibition induces PUMA via NF-κB to kill colon cancer cells. Mol Cancer Ther. 2014 May;13(5):1298-308. doi: 10.1158/1535-7163.MCT-13-0846. Epub 2014 Feb 21. PubMed PMID: 24563542; PubMed Central PMCID: PMC4013266

Lin Zhang, PhD

Tong J, X Zheng, X Tan, R Fletcher, Z Nikolovska-Coleska, J Yu and L Zhang.  Mcl-1 phosphorylation without degradation mediates sensitivity to HDAC inhibitors by liberating BH3-only proteins. Cancer Research 78: 4704-4715, 2018.
 
Chen D, J Tong, L Yang, L Wei, DB Stolz, J Yu, J Zhang and L Zhang.  PUMA amplifies necroptosis signaling by activating cytosolic DNA sensors. Proc. Natl. Acad. Sci. USA. 115: 3930-3935, 2018.
 
Knickelbein K, J Tong, D Chen, YJ Wang, S Misale, A Bardelli, J Yu and L Zhang.  Restoring PUMA induction overcomes KRAS-mediated resistance to anti-EGFR antibodies in colorectal cancer. Oncogene. 37:4599-4610, 2018.
 
Fletcher R, YJ Wang, RE Schoen, OJ Finn, J Yu, and L Zhang.  Colorectal cancer prevention: immune modulation taking the stage.  BBA - Reviews on Cancer. 1869:138-148, 2018.
 
Leibowitz BJ, L Yang, L Wei, ME Buchanan, M Rachid, RA Parise, JH Beumer, JL Eiseman, RE Schoen, L Zhang and J Yu. Targeting p53-dependent stem cell loss for intestinal chemoprotection. Science Translational Medicine. Feb 7;10(427). pii: eaam7610. doi: 10.1126/scitranslmed.aam7610, 2018.
 
Tong J, P Wang, S Tan, D Chen, Z Nikolovska-Coleska, F Zou, J Yu and L Zhang. Mcl-1 degradation is required for targeted therapeutics to eradicate colon cancer cells. Cancer Research 77: 2512-2521, 2017.
Wei L, BJ Leibowitz, X Wang, M Epperly, J Greenberger, L Zhang and J Yu. Inhibition of CDK4/6 protects against radiation-induced intestinal injury in mice.  Journal of Clinical Investigation 126:4076-4087, 2016.
 
Tong J, S Tan, F Zou, J Yu and L Zhang. FBW7 mutations mediate resistance of colorectal cancer to targeted therapies by blocking Mcl-1 degradation. Oncogene; 36:787-796, 2016.
Misale S, I Bozic, J Tong, A Peraza-Penton, A Lallo, F Baldi, KH Lin, M Truini, L Trusolino, A Bertotti, F Di Nicolantonio, MA Nowak, L Zhang, KC Wood and A Bardelli.  Vertical suppression of the EGFR pathway prevents onset of resistance in colorectal cancers.  Nature Communications 2015 Sep 22;6:8305. doi: 10.1038/ncomms9305, 2015.
 
Leibowitz B, W Qiu , ME Buchanan, F Zou, PV Vernon, MP Moyer, XM Yin, RE Schoen, J Yu and L Zhang. BID mediate selective killing of APC-deficient cells in intestinal tumor suppression by non-steroidal anti-inflammatory drugs. Proc. Natl. Acad. Sci. USA.  111:16520-16525, 2014.
Chen D, L Wei, J Yu and L Zhang. Regorafenib inhibits colorectal tumor growth through PUMA-mediated apoptosis. Clinical Cancer Research 20: 3472-3484, 2014.
Qiu W, B Wu, X Wang, M Buchanan, MD Regueiro, D Hartman, RE Schoen, J Yu and L Zhang. PUMA-mediated intestinal epithelial apoptosis contributes to ulcerative colitis in humans and mice. Journal of Clinical Investigation. 121:1722-1732, 2011.
Qiu W, X Wang, B Leibowitz, H Liu, N Barker, H Okada, N Oue, W Yasui, H Clevers, RE Schoen, J Yu and L Zhang. Chemoprevention by nonsteroidal anti-inflammatory drugs eliminates oncogenic intestinal stem cells via SMAC-dependent apoptosis. Proc Natl Acad Sci USA 107:20027-20032, 2010.