AddressJohn D. Dingell VA Medical Center 4646 John R. Detroit, MI 48201
4646 John R.
John D. Dingell VA Medical Center
Detroit, MI 48201
- Apoptosis signaling by CARP-1.
- Cell growth inhibition by CARP-1-inducing Small molecule(s).
Research in our laboratory focuses on elucidating pathways regulating cellular growth and apoptosis. By utilizing a functional gene-knockout approach, we identified and characterized a novel, apoptosis inducing protein termed CARP-1/CCAR1. CARP-1 regulates cell-growth inhibitory and apoptosis-promoting signals by chemotherapy drug adriamycin, as well as a novel class of apoptosis-inducing adamantyl retinoids. CARP-1 also regulates epidermal growth factor (EGFR)-dependent signaling events since inhibition of EGFR results in increased levels of CARP-1 and apoptosis. CARP-1 is a tyrosine as well as serine phoshorylated protein that functions in part by interacting with multiple regulators of cell growth and apoptosis signaling. The growing list of CARP-1 interacting proteins include the tumor suppressor protein p53, cell cycle regulatory Anaphase Promoting Complex (APC)-2, nuclear factor kappa B upstream kinase subunit gamma (IKKgamma/NEMO), stress-activated map kinase p38, nuclear receptors of steroid/thyroid superfamily, 14-3-3, TAZ, and p21Rac-1 proteins. Our data from biopsies of human breast and colon cancers, and lymphomas suggest an inverse correlation of CARP-1 expression with tumor grades, indicating a potential tumor suppressor property of CARP-1. Administration of peptide(s) derived from CARP-1 suppresses growth of human breast cancer and lymphoma cells in vitro, as well as of tumor xenografts. The molecular complexity of cancers and therapy-associated side effects often limit effectiveness of many therapies, and warrant development of new agents for specific molecular targets, while minimizing off-target effects. Our long-term goal is to develop mechanism-based novel, safer and effective targeted anti-cancer therapies.
Venkatesh J, Sekhar SC, Cheriyan VT, Muthu M, Meister P, Levi E, Dzinic S, Gauld JW, Polin LA, Rishi AK. Antagonizing binding of cell cycle and apoptosis regulatory protein 1 (CARP-1) to the NEMO/IKKγ protein enhances the anticancer effect of chemotherapy. J. Biol. Chem.2020; 295: 3532-52.
Sekhar S, Venkatesh J, Cheriyan VT, Muthu M, Levi E, Assad H, Meister P, Undyala VV, Gauld JW, Rishi AK. A H2AX-CARP-1 interaction regulates apoptosis signaling following DNA damage. Cancers (Basel) 2019;11:221.
Cheriyan, V.T., Alsaab, H., Sekhar, S., Venkatesh, J., Mondal, A., Vhora, I., Sau, S., Muthu, M., Polin, L.A., Levi, E., Bepler, G., Iyer, A.K., Singh, M., Rishi, A.K. A CARP-1 functional mimetic compound is synergistic with BRAF-targeting in non-small cell lung cancers. Oncotarget 2018;9:29680-97.
Cheriyan, V.T., Alsaab, H., Sekhar, S., Stieber, C., Kesharwani, P., Sau, S., Muthu, M., Polin, L.A., Levi, E., Iyer, A.K., Rishi, A.K. A CARP-1 functional mimetic loaded vitamin E-TPGS micellar nano-formulation for inhibition of Renal Cell Carcinoma. Oncotarget 2017;8:104928-45.
Cheriyan, V.T., Muthu, M., Sekhar, S., Patel, K., Larsen, S.D., Rajeswaran, W., Polin, L. A., Levi, E., Singh, M., and Rishi, A.K. CARP-1 functional mimetics are novel inhibitors of drug-resistant triple-negative breast cancers. Oncotarget 2016;7:73370-88.
Muthu, M., Cheriyan, V.T., Rishi, A.K. CARP-1/CCAR1: A bophasic regulator of cancer cell growth and apoptosis. Oncotarget 2015;6:6499-510.
Muthu, M., Somagoni, J.M., Cheriyan, V.T., Munie, S., Levi, E., Ashour, A.E., Alafeefy, A.M., Sochacki, P., Polin, L.A., Reddy, K.B., Larsen, S.D., Singh, M., and Rishi, A.K. Identification and testing of novel CARP-1 functional mimetic compounds as inhibitors of non-small cell lung and triple-negative breast cancers. J. Biomed. Nanotechnol. 2015;11:1608-27.
MSc Biochemistry: University College of London, University of London, United Kingdom
PhD Molecular Biology: Imperial College of Science, Technology, and Medicine, University of London, UK
Post-Doc: Massachusetts Institute of Technology, Cambridge, Massachusetts
Post-Doc: Brigham & Women's Hospital, Harvard, Cambridge, Massachusetts
CB7220 Molecular Biology of Cancer Development
CB7300 Special Topics - F31 Grant Writing Course
CB7460 Mechanism of Neoplasia: Alterations to Cellular Signaling (Course Director)