p53-regulated SESN1 and SESN2 regulate cell proliferation and cell death through control of STAT3.

Abstract

Sestrin1 and Sestrin2 (SESN1&2) are evolutionarily conserved, stress-responsive proteins that regulate cell growth and viability. The primary target of Sestrins is the mTORC1 protein kinase, an activator of anabolic processes and an autophagy inhibitor. Our previous studies showed that inactivating SESN1&2 in lung adenocarcinoma A549 cells accelerates cell proliferation and confers resistance to cell death without affecting mTORC1 activity, suggesting that SESN1&2 modulate cellular processes via mTORC1-independent mechanisms. This work describes a new mechanism through which SESN1&2 regulate cell proliferation and death by suppressing the STAT3 transcription factor. Normally activated in response to stress and inflammation, STAT3 is frequently overactivated in human cancers. This overactivation promotes the expression of pro-proliferative and anti-apoptotic genes that drive carcinogenesis. We demonstrate that SESN1&2 inactivation stimulates STAT3 by downregulating the PTPRD phosphatase, a protein responsible for STAT3 dephosphorylation. Our study demonstrates that SESN1&2 deficiency may cause STAT3 activation and facilitate carcinogenesis and drug resistance, making SESN1&2 reactivation a potential cancer treatment strategy.