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Pterostilbene Sensitizes Cisplatin-Resistant Human Bladder Cancer Cells with Oncogenic HRAS
Yi-Ting Chen1, Zi-Yi Huang2, Han-Hsuan Tang3
1Department of Human Development and Family Studies, National Taiwan Normal University, Taipei 106, Taiwan.
Abstract:
Analysis of various public databases revealed that HRAS gene mutation frequency and mRNA expression are higher in bladder urothelial carcinoma. Further analysis revealed the roles of oncogenic HRAS, autophagy, and cell senescence signaling in bladder cancer cells sensitized to the anticancer drug cisplatin using the phytochemical pterostilbene. A T24 cell line with the oncogenic HRAS was chosen for further experiments. Indeed, coadministration of pterostilbene increased stronger cytotoxicity on T24 cells compared to HRAS wild-type E7 cells, which was paralleled by neither elevated apoptosis nor induced cell cycle arrest, but rather a marked elevation of autophagy and cell senescence in T24 cells. Pterostilbene-induced autophagy in T24 cells was paralleled by inhibition of class I PI3K/mTOR/p70S6K as well as activation of MEK/ERK (a RAS target) and class III PI3K pathways. Pterostilbene-induced cell senescence on T24 cells was paralleled by increased pan-RAS and decreased phospho-RB expression. Coadministration of PI3K class III inhibitor 3-methyladenine or MEK inhibitor U0126 suppressed pterostilbene-induced autophagy and reversed pterostilbene-enhanced cytotoxicity, but did not affect pterostilbene-elevated cell senescence in T24 cells. Animal study data confirmed that pterostilbene enhanced cytotoxicity of cisplatin plus gemcitabine. These results suggest a therapeutic application of pterostilbene in cisplatin-resistant bladder cancer with oncogenic HRAS.
Insights
This study shows pterostilbene enhances bladder cancer cell sensitivity to cisplatin by inducing autophagy and senescence, particularly in cells with HRAS mutations. This suggests a new therapeutic strategy for resistant bladder cancers.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- HRAS gene mutations and elevated expression are common in bladder urothelial carcinoma.
- Oncogenic HRAS, autophagy, and senescence pathways play roles in bladder cancer drug resistance.
Purpose of the Study:
- To investigate the effects of pterostilbene on bladder cancer cells with oncogenic HRAS, focusing on sensitization to cisplatin.
- To elucidate the molecular mechanisms underlying pterostilbene's action, including autophagy and senescence signaling.
Main Methods:
- Utilized T24 bladder cancer cell line with oncogenic HRAS and HRAS wild-type E7 cells.
- Administered pterostilbene alone and in combination with cisplatin.
- Analyzed cell cytotoxicity, apoptosis, cell cycle arrest, autophagy, senescence, and key molecular pathways (PI3K/mTOR, MEK/ERK, RAS/RB).
- Conducted animal studies with pterostilbene, cisplatin, and gemcitabine.
Main Results:
- Pterostilbene significantly increased cytotoxicity in T24 cells, mediated by autophagy and senescence, not apoptosis or cell cycle arrest.
- Pterostilbene modulated PI3K/mTOR, MEK/ERK, and class III PI3K pathways, and affected pan-RAS and phospho-RB expression.
- Inhibitors of autophagy and MEK partially reversed pterostilbene's effects on cytotoxicity but not senescence.
- Animal studies confirmed pterostilbene enhances the efficacy of cisplatin and gemcitabine.
Conclusions:
- Pterostilbene shows therapeutic potential in sensitizing cisplatin-resistant bladder cancer with oncogenic HRAS.
- The study highlights the roles of pterostilbene-induced autophagy and senescence in overcoming drug resistance.
