Esophageal squamous cell carcinoma (ESCC) is one of the deadliest
digestive system cancers worldwide lacking effective therapeutic strategies. Recently, it has been found that the natural product
celastrol plays an anti-
cancer role in several human
cancers by inducing cell cycle arrest and apoptosis. However, it remains elusive whether and how
celastrol suppresses
tumor growth of ESCC. In the present study, for the first time, we demonstrated that
celastrol triggered both extrinsic and intrinsic apoptosis pathways to diminish the
tumor growth of ESCC in vivo and in vitro. Mechanistic studies revealed that
celastrol coordinatively induced DR5-dependent extrinsic apoptosis and Noxa-dependent intrinsic apoptosis through transcriptional activation of ATF4 in ESCC cells. Furthermore, we found that the FoxO3a-Bim pathway was involved in the intrinsic apoptosis of ESCC cells induced by
celastrol. Our study elucidated the
tumor-suppressive efficacy of
celastrol on ESCC and revealed a previously unknown mechanism underlying
celastrol-induced apoptosis, highlighting
celastrol as a promising apoptosis-inducing therapeutic strategy for ESCC.