Abstract 4608: Autophagy is required for prostate cancer progression.

Abstract

Abstract Autophagy (also referred to as macroautophagy) is a self-catabolic process that maintains intracellular homeostasis and prolongs cell survival by the autophagosomic-lysosomal degradation of cytoplasmic contents during metabolic stress or nutrient starvation. Inactivation of PTEN tumor suppressor function is a common characteristic of human prostate cancer that leads to the upregulation of the PI3K/Akt/mTOR signaling pathway, and has emerged as promising candidate for targeted therapies. mTOR is one of the upstream regulators of autophagy, therefore, inhibiting the PI3K/Akt/mTOR axis putatively stimulates autophagy. However, the role of autophagy in cancer is complex, acting both as a tumor suppressor and promoter, and its role in prostate tumorigenesis remains to be defined. Here we demonstrate that prostate cancer is dependent on autophagy for its growth and progression through the use genetically modified mouse models of prostate cancer. We had previously reported a conditional knockout mouse model in which homozygous deletion of PTEN lead to the stage-specific development of invasive adenocarcinoma. Characterization of tumors from the mice showed that although autophagy was suppressed early in tumor development, tumors eventually restored autophagic function despite increased PI3K/Akt/mTOR signaling. To determine the effect of defective autophagy on prostate cancer progression, we generated prostate-specific conditional double knockout mice harboring both inactivated PTEN and ATG7, a key regulator for the formation of autophagosomes. Prostate-specific inactivation of ATG7 function alone did not result in changes to the development or function of the prostate gland. Prostate-specific inactivation of both PTEN and ATG7 led to the early development of prostate adenocarcinoma similar to homozygous PTEN-mutant mice. However, prostate tumors failed to progress and showed regression. Our data suggests that impaired autophagy can be induced independent of mTOR and defective autophagy contributes to suppress tumor progression. Thus, our findings support the role of autophagy as a therapeutic target for advance prostate cancer. Citation Format: Marco A. De Velasco, Yurie Kura, Naomi Ando, Emiko Fukushima, Yuji Hatanaka, Yutaka Yamamoto, Nobutaka Shimizu, Kazuhiro Yoshimura, Masahiro Nozawa, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura. Autophagy is required for prostate cancer progression. [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 4608. doi:10.1158/1538-7445.AM2013-4608