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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.

Lin Zhang, PhD

The immediate goal of our research is to understand how anticancer drugs kill cancer cells, and more importantly, why they fail so often.  In the long term, we will attempt to use this knowledge to identify novel molecular targets and treatment strategies to improve cancer chemotherapy and chemoprevention.

Cell death in anticancer therapies

Our research program has centered on several molecules that control discrete steps of programmed cell death. The first one, PUMA, is a downstream target of the tumor suppressor p53 and a BH3-only Bcl-2 family protein.  PUMA is required for DNA damage-induced and p53-dependent apoptosis, and also plays a key role in apoptosis induced by several targeted anticancer drugs.  The second one, SMAC, is a mitochondrial apoptogenic protein and a caspase activator.  SMAC helps to execute apoptosis induced by anticancer drugs via a mitochondrial feedback loop.  Regulators of non-apoptotic cell death, such as the autophagy inducer Beclin 1 and the necrosis regulator RIPK3, have also been studied.  Through analyses of these molecules and their associated protein networks, we try to gain deep understanding on how cell death is initiated and executed in human cancer cells, why some cancer cells are not sensitive to anticancer drugs, and what can be done to restore their sensitivity.

Oncogenic stem cells as the target of cancer chemoprevention

Prevention of human cancer through the use of chemical agents such as non-steroidal anti-inflammatory drugs (NSAIDs) has emerged as a promising strategy to reduce morbidity and mortality of cancer.  Our recent studies showed that intestinal stem cells that have acquired oncogenic alterations are targeted by NSAIDs in chemoprevention of colon cancer.  We are investigating how NSAIDs trigger apoptosis in such oncogenic stem cells, and if induction of apoptosis is critical for the chemopreventive effects of NSAIDs.  We will also determine if apoptosis regulators can be used as markers to predict outcomes of chemoprevention of cancer patients, and if manipulation of apoptosis regulators can be used to improve the chemopreventive effects of NSAIDs.

Manipulation of cell death regulators

To target PUMA, we have developed a high-throughput screening system for identifying small molecules that can activate PUMA in p53-deficient cancer cells.  In collaboration with the Pittsburgh Drug Discovery Institute, we will screen compound libraries to identify novel PUMA inducers.  We have also identified and characterized small molecules that mimic the functional domains of PUMA and SMAC.  Efforts are undertaken to apply these small molecules to chemotherapy and chemoprevention.

Headshot of Kyle Knickelbein
Kyle Knickelbein
Graduate Student Researcher

Headshot of Lin Zhang, PhD
Lin Zhang, PhD

Kyle Knickelbein

Journal Articles

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

Ning Wei, PhD

Journal Articles

Wei N, Li J, Fang C, Chang J, Chu E andSchmitz J. Targeting colon cancer with the novel STAT3 inhibitor. Oncogene 38(10):1676-1687, 2019.
Pal R, Wei N, Song N, Wu S, Kim RS, Wang Y, Gavin PG, Lucas PC, Srinivasan A, Allegra CJ, et al. Molecular subtypes of colorectal cancer in pre-clinical models show differential response to targeted therapies: Treatment implications beyond KRAS mutations. Plos One 13(8): e0200836, 2018.
Wang Y, Sun H, Xiao Z, Zhang G, Zhang D, Bao X, Li F, Wu S, Gao Y and Wei N. DNA damage and apoptosis induced by a potent orally podophyllotoxin derivative in breast cancer. Cell Communication and Signaling 16(1):52, 2018.
Wei N, Chu E, Wipf P and Schmitz JC. Protein kinase D as a potential chemotherapeutic target for colorectal cancer. Molecular Cancer Therapeutics 13(5):1130-1141, 2014.
Wei N, Liu GT, Chen XG, Liu Q, Wang FP and Sun H. H1, a derivative of Tetrandrine, exerts anti-MDR activity by initiating intrinsic apoptosis pathway and inhibiting the activation of Erk1/2 and Akt1/2. Biochemical Pharmacology 82(11):1593-1603, 2011.

Lin Zhang, PhD

Journal Articles

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.
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.
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.
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.