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Jolkinolide B sensitizes bladder cancer to mTOR inhibitors via dual inhibition of Akt signaling and autophagy
- Source :
- Cancer letters. 526
- Publication Year :
- 2021
-
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 are 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.
- Subjects :
- MAPK/ERK pathway
Male
Cancer Research
Transfection
Paraptosis
Mice
Cell Line, Tumor
medicine
Autophagy
Animals
Humans
Protein kinase B
Bladder cancer
Everolimus
Chemistry
Cancer
MTOR Inhibitors
medicine.disease
Temsirolimus
Oncology
Urinary Bladder Neoplasms
Cancer research
Diterpenes
Proto-Oncogene Proteins c-akt
medicine.drug
Drugs, Chinese Herbal
Signal Transduction
Subjects
Details
- ISSN :
- 18727980
- Volume :
- 526
- Database :
- OpenAIRE
- Journal :
- Cancer letters
- Accession number :
- edsair.doi.dedup.....6a31b0bbf74b43754d9a2d99aa3ad41b