Singh Lab

The Singh lab's research projects revolve around glutathione transferases (GSTs), which play an important role in drug metabolism and cellular defense against environmental and dietary chemical carcinogens (e.g., polycyclic aromatic hydrocarbons or PAHs). One of his research projects focuses on toxicological relevance of polymorphism at the GST Pi gene locus (a subclass of GSTs) in susceptibility to PAH induced cancers. These studies are based on his findings that allelic variants of GST Pi (hGSTP1-1) differ remarkably in their ability to detoxify PAH carcinogens. His colleagues are trying to generate knock-in mice for hGSTP1 variants to investigate the in vivo relevance of hGSTP1 polymorphism in defense against PAH carcinogens in an animal model.

GST-catalyzed conjugation reactions are not always advantageous. For example, a number of clinically used alkylating anticancer drugs are substrates for hGSTP1-1, and its overexpression in cancer cells confers resistance to these drugs. Dr. Singh and his colleagues have shown that the allelic variants of hGSTP1-1 differ in their activity toward certain alkylating agents. Studies are in progress to test the hypothesis that individuals homozygous for high-activity allele of hGSTP1-1 may be at a greater risk for developing resistance to alkylating agents than heterozygotes or homozygotes for the low-activity allele.

The Singh laboratory is also interested in investigating the anticarcinogenic effects of certain natural agents found in edible plants, including organosulfides from garlic and isothiocyanates from cruciferous vegetables such as broccoli. His more recent studies have revealed that these dietary phytochemicals can not only prevent chemically induced cancers but also inhibit the growth of tumor cells in vitro in culture and in vivo in nude mouse. Studies are in progress to elucidate the molecular mechanism for anti-neoplastic effects of these widely consumed dietary agents.

Below displays the Research Details from the profile of each member of the lab.

Shivendra Singh, PhD

Cancer chemoprevention is a relatively new but rapidly emerging sub-discipline in oncology and signifies the use of natural or synthetic agents to reverse or delay the process of carcinogenesis. Long latency of most epithelial cancers presents a large window of opportunity for intervention to prevent or slow disease progression. The research interests of the Singh laboratory include molecular characterization of novel cancer chemopreventive agents and rational design of mechanism-driven combination chemoprevention regimens. Cellular and transgenic animal models are used to screen potential cancer chemopreventive constituents from dietary and medicinal plants. Cutting edge cellular, molecular biological, Omics (metabolomics and proteomics), structural biology, and imaging techniques (MRI and bioluminescence) are used to (a) determine the mechanism of action of promising cancer chemopreventive agents, (b) monitor effects on cancer progression, and

(c) identify biomarkers predictive of tissue exposure and possibly response. Some of the agents under active investigation in the Singh laboratory include: cruciferous vegetable-derived isothiocyanates, garlic-derived organosulides, and medicinal plant constituent withaferin A. As an example, recent published work from the Singh laboratory indicates suppression of glycolysis in mammary cancer prevention by withaferin A in a transgenic mouse model (JNCI, In Press, 2013). Likewise, complementary cellular and molecular biological, targeted proteomics, and molecular modeling techniques were used to identify beta-tubulin as a novel target of cancer cell growth arrest by withaferin A (WA).

Eun-Ryeong Hahm, PhD
Reseach Instructor

Krishna Singh, PhD
Postdoctoral Associate

Shivendra Singh, PhD
Professor and UPMC Chair in Cancer Prevention Research

Shivendra Singh, PhD

Journal Articles

Hahm ER, J Lee, SH Kim, A Sehrawat, JA Arlotti, SS Shiva, R Bhargava and SV Singh.  Metabolic alterations in mammary cancer prevention by withaferin A in a clinically-relevant mouse model.  J Natl Cancer Inst 105:1111-1122, 2013.
Singh SV, SH Kim, A Sehrawat, JA Arlotti, ER Hahm, K Sakao, JH Beumer, RC Jankowitz, K Chandra-Kuntal, J Lee, AA Powolny and R Dhir.  Biomarkers of phenethyl isothiocyanate-mediated mammary cancer chemoprevention in a clinically relevant mouse model.  J Natl Cancer Inst 104:1228-1239, 2012.
Powolny AA, A Bommareddy, ER Hahm, DP Normolle, JH Beumer, JB Nelson and SV Singh.  Chemopreventative potential of the cruciferous vegetable constituent phenethyl isothiocyanate in a mouse model of prostate cancer.  J Natl Cancer Ins 103:571-584, 2011.
Xiao D and SV Singh.  p66shc is indispensable for phenethyl isothiocyanate-induced apoptosis in human prostate cancer cells.  Cancer Res 70:3150-3158, 2010.
Bommareddy A, ER Hahm, D Xiao, AA Powolny, AL Fisher, Y Jiang and SV Singh.  Atg5 regulates phenethyl isothiocyanate-induced autophagic and apoptotic cell death in human prostate cancer cells.  Cancer Res 69:3704-3712, 2009.