Pharmacological vitamin C inhibits mTOR signaling and tumor growth by degrading Rictor and inducing HMOX1 expression.

Pharmacological vitamin C (VC) is a potential natural compound for cancer treatment. However, the mechanism underlying its antitumor effects remains unclear. In this study, we found that pharmacological VC significantly inhibits the mTOR (including mTORC1 and mTORC2) pathway activation and promotes GSK3-FBXW7-mediated Rictor ubiquitination and degradation by increasing the cellular ROS. Moreover, we identified that HMOX1 is a checkpoint for pharmacological-VC-mediated mTOR inactivation, and the deletion of FBXW7 or HMOX1 suppresses the regulation of pharmacological VC on mTOR activation, cell size, cell viability, and autophagy. More importantly, it was observed that the inhibition of mTOR by pharmacological VC supplementation in vivo produces positive therapeutic responses in tumor growth, while HMOX1 deficiency rescues the inhibitory effect of pharmacological VC on tumor growth. These results demonstrate that VC influences cellular activities and tumor growth by inhibiting the mTOR pathway through Rictor and HMOX1, which may have therapeutic potential for cancer treatment. Author summary: Vitamin C (VC) is an essential nutrient for human beings, and pharmacological VC is a potential natural compound for cancer treatment. The mTOR pathway plays an important role in tumor formation and progress, but whether VC can have an anticancer effect on the mTOR pathway or not remains unclear. In this study, we found that pharmacological VC blocked the activation of the mTOR pathway and tumor growth by degrading Rictor and inducing HMOX1 expression. Mechanistically, VC induced intracellular ROS, which can promote the expression of HMOX1 and GSK3-FBXW7-mediated ubiquitination of Rictor. Moreover, functional analysis demonstrated that pharmacological VC regulated the viability, autophagy, and apoptosis of cancer cells. Most importantly, the xenografted mouse models showed that VC acted as an anticancer agent by inhibiting the activity of the mTOR pathway. Thus, our study revealed a new anticancer mechanism of VC by inhibiting the mTOR pathway, thereby providing the evidence for the therapeutic potential of VC, when combined with other drugs, in cancer treatment. [ABSTRACT FROM AUTHOR]