Research
Srivastava, Rakesh, Ph.D.
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Contact: rakesh.srivastava@uthct.edu
Education:
1994, Ph.D. Endocrinology, University of Guelph, Guelph, Ontario, Canada.
1990, M.S. Biochemistry, Memorial University of Newfoundland, St. John’s, NF, Canada.
Research Interest:
Molecular mechanisms of apoptosis in cancer; drug discovery and development of novel compounds for human diseases; chromatin modification and its effect on pathogenesis; mitochondrial functions and cellular homeostasis; cancer prevention by naturally occuring compounds.
Current Projects:
- Molecular mechanisms and therapeutic potential of TRAIL.
- Clinical significance of histone deacetylase inhibitors in cancer.
- Regulation of death receptor pathway of apoptosis by small molecular weight compounds for the treatment of human diseases.
- Molecular mechansims and preclinical evaluations of chemopreventive agents.
- Cigarette smoke and lung cancer pathogenesis.
Lay Summary:
Apoptosis is a form of cell death which occurs during both physiological and pathological conditions. It plays a major role in tissue homeostasis, removal of activated immune cells after an infection, and deletion of oncogenitically or virally transformed cells. Accordingly, disturbances in the execution and processing of apoptosis can lead to many human diseases such as cancer, HIV and neurodegenerative disorders. Apoptosis is tightly regulated by the ratio of proapoptotic and antiapoptotic proteins, deviations from normal equilibrium of these regulatory proteins are often an improtant contributing factor in tumorigenesis. Failure in the execution of apoptotic pathway by anticancer therapy may result in tumor escape.
Research Overview:
Apoptosis can be initiated by an intrinsic pathway involving mitochondrial activation or by an extrinsic pathway (death receptor pathway) through the binding of specific protein ligands to transmembrane receptors belonging to the tumor necrosis factor (TNF) superfamily to death receptors. The death receptorathways plays amajor role during organ development, in the immune system, and also in tumorigenesis. Resistance to apoptosis is generally a result of constitutive or regulated expression of an array of proteins (e.g. Bcl-2 family members, death receptors, kinases, IAPs) that target these apoptotic signaling pathways. The main goals of my research are: (1) to examine the molecular mechanisms of apoptosis; (2) to develop new therapies for human diseases such as cancer; (3) to develop cancer chemopreventive agents; and (4) to examine the effects of cigarette smoke on lung pathogenesis.
Selected Papers and Abstracts:
- Fandy TE, Shankar S, Ross DD, Sausville E, Srivastava RK. 2005. Interactive Effects of HDAC inhibitors and TRAIL on apoptosis are associated with changes in mitochondrial functions and expressions of cell cycle regulatory genes in multiple myeloma. Neoplasia 7: 646-57.
- Singh, TR, Shankar S, Srivastava RK. 2005. HDAC inhibitors enhance the poptosis-inducing potential of TRAIL in breast carcinoma. Oncogene 24: 4609-23.
- Shankar S, Chen X, Srivastava RK. 2005. Effects of sequential treatments with chemotherapeutic drugs followed by TRAIL on prostate cancer in vitro and in vivo. Prostate 62: 165-186.
- Shankar S, Singh TR, Srivastava RK. 2004. Ionizing radiation enhances the therapeutic potential of TRAIL in prostate cancer in vitro and in vivo: intracellular mechanisms. Prostate 61: 35-49.
- Shankar S, Singh TR, Chen X, Thakkar H, Firnin J, Srivastava RK. 2004. The sequential treatment with ionizing radiation followed by TRAIL/Apo-2L reduces tumor growth and induces apoptosis of breast tumor xenografts in nude mice. Inter J. Oncol. 24: 1133-40.
- Singh TR, Shankar S, Chen X, Asim M, Srivastava RK. 2003. Synergistic interactions of chemotherapeutic drugs and TRAIL on apoptosis and on regression of breast carcinoma in vivo. Cancer Res. 64: 6675-6686.
- Kandasamy K, Srinivasula SM, Alnemri ES, Thompson CB, Korsmeyer SJ, Bryant JL, Srivastava, RK. 2003. Involvement of proapoptotic molecules Bax and Bak in tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced mitochondrial disruption and apoptosis: Differential regulation of cytochrome c and Smac/DIABLO release. Cancer Res. 63:1712-21.
- Chen X, Kandasamy K, Srivastava RK. 2003. Differential roles of RelA (p65) and c-Rel subunits of nuclear factor kappa B (NF k B) in tumor necrosis factor-related apoptosis-inducing ligand signaling. Cancer Res. 63:1059-66.
- Kandasamy K, Srivastava RK. 2002. Role of the Phosphatidyl 3’-Kinase/PTEN/Akt Kinase Pathway in TRAIL-induced Apoptosis in Non-Small Cell Lung Cancer (NSCLC) cells. Cancer Res. 62: 4929-4937.
- Chen X, Thakkar H, Tyan F, Gim S, Robinson H, Lee C, Pandey SK, Nwokorie C, Onwudiwe N, Srivastava RK. 2001. Constitutively active Akt is an important regulator of TRAIL sensitivity in prostate cancer. Oncogene 20: 6073-6083.
