Abstract 1835: Nqo1 ablation inhibits activation of the PI3K/Akt and MAPK/ERK pathways and blocks metabolic adaptation in hepatocellular carcinoma

Abstract

Abstract According to the World Health Organization, hepatocellular carcinoma (HCC) is the 2nd leading cause of cancer related deaths worldwide. HCC is highly resistant to conventional chemotherapies; therefore, identification of specific molecular targets for the development of targeted therapies is indispensable. Cancer cells undergo metabolic adaptation to sustain uncontrolled proliferation and depends on the high rate of glycolysis and glutaminolysis. Hence, identifying and targeting proteins that assist cancer cells in metabolic reprogramming is an effective strategy to block their proliferation. We detected a strong upregulation of NAD(P)H Quinone Dehydrogenase 1 (Nqo1), a cytosolic flavoprotein, in vivo in mouse and human liver tumors as well as in liver cancer cell lines in vitro. Knockdown of Nqo1 in liver cancer cells by shRNA caused a significant downregulation of both glycolytic and glutaminolysis genes, impaired cell proliferation, colony formation and in vivo xenograft tumor growth. Nqo1-/- mice with HCC displayed significant reduction in tumor number, size and growth. In Nqo1+/+ mice, histological analysis of liver tumors revealed large tumor cells with hyperchromatic nuclei in a compact growth pattern, whereas Nqo1-/- livers appeared normal. Hyper-activated PI3K/Akt and MAPK/ERK signaling pathways play central role in cancer cell metabolic adaptation since their downstream effectors such as Akt and c-Myc control most of the glycolytic and glutaminolysis genes. Interestingly, at the molecular level, Nqo1 knockdown caused strong upregulation of the tumor suppressor PTEN, and enhanced activation of the serine/threonine phosphatase PP2A, leading to impaired activation of the PI3K/Akt and MAPK/ERK/c-Myc pathways. Our findings indicate that, by targeting PP2A and PTEN, Nqo1 enhances the expression and/or activity of PDK1, Akt, ERK1/2 and c-Myc and promotes cancer cell metabolic reprogramming and hence may function as a key therapeutic target for HCC inhibition. Citation Format: Manali Dimri, Ashley Humphries, Archana Laknaur, Sawsan Elattar, Ashok Sharma, Ravindra Kolhe, Ande Satyanarayana. Nqo1 ablation inhibits activation of the PI3K/Akt and MAPK/ERK pathways and blocks metabolic adaptation in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1835.