Jolkinolide B sensitizes bladder cancer to mTOR inhibitors via dual inhibition of Akt signaling and autophagy. (1st February 2022)

• Record Type: Journal Article
• Authors: Sang, Jun; Gan, Lu; Zou, Ming-Feng; Lin, Zi-Jun; Fan, Run-Zhu; Huang, Jia-Luo; Li, Wei; Tang, Gui-Hua; Yin, Sheng
• Is Part Of: Cancer letters. Volume 526(2022)
• Page Start: 352
• Page End: 362
• Publication Date: 2022-02-01
• Subjects: Natural diterpenoid -- Drug resistance -- Reactive oxygen species -- Paraptosis -- Apoptosis; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2021.11.014
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: The monotherapy of mTOR inhibitors (mTORi) in cancer clinical practice has achieved limited success due to the concomitant activation of compensatory pathways, such as Akt signaling and cytoprotective autophagy. Thus, the combination of mTORi and the inhibitors of these pro-survival pathways has been considered a promising therapeutic strategy. Herein, we report the synergistic effects of a natural anti-cancer agent Jolkinolide B (JB) and mTORi (temsirolimus, rapamycin, and everolimus) for the effective treatment of bladder cancer. A mechanistic study revealed that JB induced a dual inhibition of Akt feedback activation and cytoprotective autophagy, potentiating the anti-proliferative efficacy of mTORi in both PTEN-deficient and cisplatin-resistant bladder cancer cells. Meanwhile, mTORi augmented the pro-apoptotic and pro-paraptotic effects of JB by reinforcing JB-activated endoplasmic reticulum stress and MAPK pathways. These synergistic mechanisms were related to cellular reactive oxygen species accumulation. Our study suggests that dual inhibition of Akt feedback activation and cytoprotective autophagy is an effective strategy in mTORi-based therapy, and JB + mTORi combination associated with multiple anti-cancer mechanisms and good tolerance in mouse models may serve as a promising treatment for bladder cancer. Highlights: JB sensitizes resistant bladder cancer cells to mTORi in vitro and in vivo. JB blocks mTORi-induced Akt feedback activation and cytoprotective autophagy. mTORi enhances the pro-apoptotic and pro-paraptotic effects of JB. The mutual potentiation of JB and mTORi involves ROS accumulation.