Abstract 1687: Frequent inactivation of the Mieap-regulated mitochondrial quality control in colorectal cancer.

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 in a process known as MALM (Mieap-induced Accumulation of Lysosome-like organelles within Mitochondria) or MIV (Mieap-Induced Vacuole), 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 57 cases of primary colorectal cancer. Of the 57 patients, Mieap and BNIP3 promoter methylation was observed in 5 (8.8%) and 26 (45.6%) patients, respectively. A p53 mutation was detected in 4 (18%) of the 22 patients with either Mieap or BNIP3 promoter methylation whereas it was found in 9 (52%) of the 17 patients with neither Mieap nor BNIP3 promoter methylation, implying that the p53/Mieap/BNIP3 pathway in the Mieap-regulated MQC is inactivated in at least 80% of colorectal cancer cases. Hypoxia induced MALM in the colorectal cancer cell line LS174T (wild-type p53, Mieap-positive, BNIP3-positive). In vitro knockdown of p53, Mieap, or BNIP3 in the LS174T cells 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 under hypoxic conditions. These results suggest that the Mieap-regulated MQC function plays a critical role in tumor suppression in colorectal 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: Hiroki Kamino, Yasuyuki Nakamura, Noriaki Kitamura, Manabu Futamura, Masaki Yoshida, Ryuya Murai, Yuri Saito, Hitoya Sano, Yae Kanai, Yoshihiro Moriya, Hirofumi Arakawa. Frequent inactivation of the Mieap-regulated mitochondrial quality control in colorectal 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 1687. doi:10.1158/1538-7445.AM2013-1687