Abstract A04: Hyperactive mTOR induces neuroendocrine differentiation in LNCaP prostate cancer cell with concurrent upregulation of interferon regulatory factor 1

The PI3K-Akt-mTOR pathway is frequently activated in prostate cancer. However, the precise function of mTOR in prostate cancer progression is yet to be elucidated. Thus, in this study, we performed a gain-of-function analysis by establishing human prostate cancer LNCaP stable line that expresses hyperactive mTOR (LNCaP-mTOR). Hyperactive mTOR induced neuroendocrine differentiation (NED) that can be suppressed by an mTOR inhibitor, rapamycin. Subsequent comprehensive mass spectrometric analysis in conjunction with cascade analysis indicates that the members of interferon regulator factor (IRF) family, especially IRF1, are key transcription factors in NED of LNCaP-mTOR. Aside from its major role in immune response, IRF1 is known to be a tumor suppressor. To further investigate the function of IRF1 in NED induced by hyperactive mTOR, we disrupted the IRF1 gene in LNCaP-mTOR by CRISPR/Cas system. The disruption of the IRF1 gene resulted in an acceleration of an NED-associated morphological change, elevation of neuroendocrine cell marker, neuron specific enolase, and a partial recovery of growth arrest. These results suggest that IRF1 partially suppresses NED at downstream of hyperactive mTOR. Together, our results indicate that two seemingly contradictory events, NED and the induction of IRF1, are induced by hyperactive mTOR, giving rise to a notion that pharmacological inhibition of mTOR can be a “double-edged sword” for prostate cancer treatments. Citation Format: Mayuko Kanayama, Toshiya Hayano, Tatsuya Maeda, Shigeo Horie, Atsu Aiba. Hyperactive mTOR induces neuroendocrine differentiation in LNCaP prostate cancer cell with concurrent upregulation of interferon regulatory factor 1. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr A04.