Abstract 764: GSTP1 knockdown and inhibition impairs pancreatic ductal adenocarcinoma (PDAC) growth

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the third-leading cause of cancer-related mortalities in the Western world and continues to be a major unresolvable health problem at the start of the 21st century. Resistance to the currently available treatment options has led to development of new approaches, such as personalized medicine and immunotherapy. However, new therapeutic strategies based on the unique molecular biology and physiology of pancreatic cancer hold the greatest promise. Glutathione S-transferase pi 1 (GSTP1) is a key detoxification enzyme which metabolizes xenobiotic compounds and byproducts of cellular metabolism. GSTP1 is overexpressed in many tumors, particularly ovarian, non-small cell lung, breast, colon, and pancreas. Moreover, GSTP1 is overexpressed in drug-resistant cancer cell lines. The reasons for increased expression ratios compared to normal tissues or wild-type cell lines are not well understood. To investigate the role of GSTP1 in PDAC pathogenicity, we generated two knockdown lines of GSTP1 in metabolically diverse PDAC cells. We showed that GSTP1 knockdown impairs the growth and proliferation of PDAC cells. Additionally, GSTP1 knockdown cells exhibit elevated reactive oxygen species (ROS) levels and a prolonged G0/G1 phase of the cell cycle. Intrigued by these results, we next examined whether pharmacological inhibition with a selective GSTP1 inhibitor, Ezatiostat (TLK199), also impaired PDAC pathogenicity. Ezatiostat is a small molecule drug and is novel glutathione analog, which selectively binds and inhibits GSTP1. Ezatiostat treatment in PDAC cells recapitulated the proliferation impairments observed with genetic inactivation of GSTP1 and elevated ROS levels. Orthotopic implantation of GSTP1 knockdown cells in athymic nude mice resulted in reduced tumor weight and volume compared to the control. The growth trajectory of the tumors was monitored via Vevo-3100 ultrasound imaging system. Our preliminary data indicate enhanced sensitivity of glycolytic cancer cells towards an ROS-inducing agent and a GSTP1 inhibitor, piperlongumine (PL). Interestingly, we have found PL is less cytotoxic to cells with reduced GSTP1 levels, indicating that PL primarily works by inhibiting GSTP1 activity. Together, these data suggest that GSTP1 knockdown and inhibition impairs the growth and survival of phenotypically diverse PDAC cells in vitro and in vivo. Moreover, GSTP1 knockdown results in elevated ROS levels and an extended G0/G1 phase of the cell cycle. With these data, we propose that GSTP1 is a novel therapeutic target for PDAC. Citation Format: Rahul Raj Singh, Katie M. Reindl. GSTP1 knockdown and inhibition impairs pancreatic ductal adenocarcinoma (PDAC) growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 764.