Abstract LB-132: Frequent inactivation of the p53/Mieap/BNIP3 mitochondrial quality control pathway in gastric cancer.

Abstract

Abstract Recently, we discovered a novel mechanism for mitochondrial quality control (MQC), in which Mieap, a p53-inducible protein, controls MQC by repairing or eliminating unhealthy mitochondria via MALM (Mieap-induced Accumulation of Lysosome-like organelles within Mitochondria) or MIV (Mieap-Induced Vacuole) generation, respectively (1, 2). We also reported that two mitochondrial outer membrane proteins, BNIP3 and NIX, are essential mediators of the MALM (2, 3). To examine the role of Mieap-regulated MQC pathway in tumorigenesis, we analyzed the status of p53, Mieap, BNIP3, and NIX in 50 cases of primary gastric cancer. Of the 50 patients, Mieap and BNIP3 promoter methylation was observed in 2 (4%) and 29 (58%) patients, respectively. A p53 mutation was detected in 2 (10%) of the 20 patients with either Mieap or BNIP3 promoter methylation whereas it was found in 3 (15.8%) of the 19 patients with neither Mieap nor BNIP3 promoter methylation, implying that the p53/Mieap/BNIP3 MQC pathway is inactivated in at least 70% of gastric cancer cases. In a colorectal cancer cell line, hypoxia induced MALM. Knockdown of p53, Mieap, or BNIP3 in the cell line severely inhibited hypoxia-induced MALM, leading to the accumulation of unhealthy mitochondria and increased mitochondrial reactive oxygen species (mtROS) generation. Furthermore, the mtROS dramatically enhanced cancer migration and invasion in hypoxic conditions. These results suggest that the p53/Mieap/BNIP3 MQC pathway plays a tumor-suppressive role in gastric cancer. 1. Miyamoto Y et al. PLoS ONE 6: e16054, 2011 2. Kitamura N et al. PLoS ONE 6: e16060, 2011 3. Nakamura Y et al. PLoS ONE 7: e30767, 2012 Citation Format: Hitoya Sano, Hiroki Kamino, Yasuyuki Nakamura, Masaki Yoshida, Ryuya Murai, Yuri Saito, Manabu Futamura, Kazuhiro Yoshida, Hirofumi Arakawa. Frequent inactivation of the p53/Mieap/BNIP3 mitochondrial quality control pathway in gastric cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-132. doi:10.1158/1538-7445.AM2013-LB-132