Abstract 1333: Inactivation of NBR1 enhances sensitivity to rapamycin on human urothelial cancer cell lines through AMPK/ULK1-mediated autophagy

Abstract

Abstract Rapamycin has been highly evaluated in clinical therapeutic intervention for cancer patients as a specific inhibitor of the mammalian target of rapamycin (mTOR) kinase. Rapamycin also stimulates autophagy and mitophagy to remove damaged cells as a regulator of general autophagy. Previously, we identified increased expression of mRNA levels of NBR1 (autophagy cargo receptor) by inhibiting mTOR signaling in human urothelial cancer cell lines. Therefore, we investigated whether loss of NBR1 sensitizes human urothelial cancer cells to autophagic stimulation and stress-induced mitochondrial insults by treatment with rapamycin. NBR1-deficient cells exhibited enhanced sensitivity to rapamycin that was associated with increased autophagy and mitochondrial defects. Loss of NBR1 expression altered the cellular response to rapamycin treatment, resulting in impaired ATP homeostasis and an increase in reactive oxygen species. Moreover, rapamycin treatment also induced autophagy activity through AMPK activation in NBR1-deficient cells, which was involved in blocked mTOR signaling and activated unc-51 like autophagy activating kinase 1 (ULK1). NBR1-deficient cells exhibited profound mitochondrial dysfunction in response to rapamycin treatment as evidenced by Δψm collapse, ATP depletion, ROS accumulation and apoptosis activation. Therefore, our findings provide a rationale for rapamycin treatment of NBR1-deficient human urothelial cancer through induction of autophagy activity by regulating the AMPK/mTOR signaling pathway, indicating that NBR1 can be a potential candidate for the treatment of human urothelial cancer. (NRF-2015R1A1A1A0500110 to I.H.C., NRF-2016R1D1A1B03933826 to Y.M.W., and the Korea Health Technology R&D Project HI17C0710 to C.I.H.) Citation Format: Myeong Joo Kim, Min Ji Cho, In Ho Chang, Young Mi Whang. Inactivation of NBR1 enhances sensitivity to rapamycin on human urothelial cancer cell lines through AMPK/ULK1-mediated autophagy [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 1333.