Abstract 2776: Mitochondrial calcium uniporter in pancreatic cancer metastasis and metabolic stress resistance

Abstract

Abstract Despite recent advances in cancer diagnosis and therapeutic modalities, the prognosis for pancreatic ductal carcinoma (PDAC) remains very poor. Most PDAC patients succumb to local and distant metastasis soon after the initial diagnosis. Therefore understanding molecular mechanisms underlying PDAC metastasis is crucial to the development of more effective PDAC therapies. Here we examined the role of mitochondrial calcium uniporter (MCU), a mitochondrial inner membrane calcium channel responsible for mitochondrial Ca2+ uptake, in pancreatic cancer metastasis and progression. We discovered that MCU is overexpressed in PDAC when compared to adjacent pancreatic tissues. MCU overexpression in PDAC patients is significantly associated with PDAC lymph node metastasis, histologic grade and pTNM stage. We also found that higher levels of MCU in PDAC patients was associated with worse overall survival (OS, P<0.01) and relapse-free survival (RFS, P<0.05) after surgical resection of tumors. MCU knockdown inhibits the PDAC cell motility, invasiveness, metabolic stress resistance and chemoresistance in cell culture models and PDAC metastasis in an orthotopic xenograft mouse model. Mechanistically, MCU controls the activation of the Keap1-Nrf2 signaling pathway through promoting mitochondrial ROS production and the oxidation of mitochondrion-recruited Keap1. Our data support that MCU regulates cancer cell metabolic stress resistance and oxidative stress response to drive PDAC metastasis and progression. Inhibiting MCU expression or blocking mitochondrial calcium influx may be an attractive approach for treating metastatic PDAC. Citation Format: Xiuchao Wang, Shengchen Lin, Jianwei Sun, Jiaxin Kang, Jihui Hao, Shengyu Yang. Mitochondrial calcium uniporter in pancreatic cancer metastasis and metabolic stress resistance [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 2776.