Gambogenic acid induces Noxa-mediated apoptosis in colorectal cancer through ROS-dependent activation of IRE1α/JNK

Background: Gambogenic acid (GNA), an active component of Garcinia hanburyi Hook.f. (Clusiaceae) (common name gamboge), exerts anti-inflammatory and antitumor properties. However, the underlying mechanism of GNA in colorectal cancer (CRC) is still not well understood. Purpose: This study aimed to investigate the antitumor effects and mechanisms of GNA on CRC in vitro and in vivo. Methods: Cell viability, colony formation and cell apoptosis assays were performed to determine the antitumor effects of GNA. qRT-PCR and Western blotting were performed to evaluate the expression of genes or proteins affected by GNA in vitro and in vivo. HCT116 colon cancer xenografts and the APC(min/+) mice model were used to confirm the antitumor effects of GNA on CRC in vivo. Results: GNA induced Noxa-mediated apoptosis by inducing reactive oxygen species (ROS) generation and c-Jun N-terminal kinase (JNK) activation. Moreover, GNA triggered endoplasmic reticulum (ER) stress, which subsequently activated inositol-requiring enzyme-1 alpha (IRE1 alpha) leading to JNK phosphorylation. ROS scavenger attenuated GNA-induced IRE1 alpha activation and JNK phosphorylation. Knockdown of IRE1 alpha also prevented GNA-induced JNK phosphorylation. In vivo, GNA suppressed tumor growth and progression in HCT116 colon cancer xenografts and the APC(min/+ )mices model. Conclusion: These findings revealed that GNA induced Noxa-mediated apoptosis by activating the ROS/IRE1 alpha/JNK signaling pathway in CRC both in vitro and in vivo. GNA is therefore a promising antitumor agent for CRC treatment.