Abstract 320: Frequent inactivation of the Mieap-regulated mitochondrial quality control in pancreatic and breast cancer

Abstract

Abstract Mieap, a p53-inducible protein, controls mitochondrial quality by repairing or eliminating unhealthy mitochondria via MALM (Mieap-induced Accumulation of Lysosome-like organelles within Mitochondria) or MIV (Mieap-Induced Vacuole), respectively (1, 2). Two mitochondrial outer membrane proteins, BNIP3 and NIX are essential mediators of MALM (3). Previously, we reported that the Mieap-regulated mitochondrial quality control (MQC) pathway was inactivated in almost 80% of colorectal cancer patients. To evaluate the role of the Mieap-regulated MQC in pancreatic and breast cancer, we analyzed the status of p53, Mieap, BNIP3 and NIX in 50 cases of primary pancreatic cancer and 63 cases of primary breast cancer by examining p53 mutation and Mieap/BNIP3/NIX promoter methylation. As the result, the Mieap-regulated MQC pathway was inactivated in 71% of pancreatic and 27% of breast cancer patients. Interestingly, the BNIP3 promoter methylation was frequently detected in colorectal and pancreatic cancer patients (49% and 58%, respectively) whereas it was not detected in breast cancer patients at all (0%). Instead, the Mieap promoter methylation was highly detected in breast cancer patients (12.7%) compared to colorectal and pancreatic cancer patients (8.8% and 2.0%, respectively). These results suggest that the Mieap-regulated MQC pathway plays a critical role in tumorigenesis of pancreatic and breast cancer, and that there may be some different mechanisms between colorectal/pancreatic and breast cancers for inactivation of the Mieap-regulated MQC pathway. Inactivation of Mieap-regulated MQC pathway leads to the accumulation of unhealthy mitochondria generating high level of mitochondrial reactive oxygen species. We are now investigating whether the p53/Mieap/BNIP3 MQC pathway affects cell growth, cell motility or tumorigenicity using several pancreatic and breast cancer cell lines that are subcutaneously implanted into nude mice. In this paper, we discuss the potential role of the Mieap-regulated MQC in pancreatic and breast tumor suppression. 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, Hitoya Sano, Ryuya Murai, Yuri Saito, Manabu Futamura, Kazuhiro Yoshida, Nobuyoshi Hiraoka, Yae Kanai, Ryoji Kushima, Toyomasa Katagiri, Hirofumi Arakawa. Frequent inactivation of the Mieap-regulated mitochondrial quality control in pancreatic and breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 320. doi:10.1158/1538-7445.AM2014-320