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Published on: January 11, 2019
Suberoylanilide hydroxamic acid sensitizes human oral cancer cells to TRAIL-induced apoptosis through increase DR5
Cheng-Chang Yeh1, Yi-Ting Deng, De-Yuan Sha
1School of Dentistry, National Taiwan University Medical Center, Taipei, Taiwan.
Abstract:
Suberoylanilide hydroxamic acid has been shown to selectively induce tumor apoptosis in cell cultures and animal models in several types of cancers and is about as a promising new class of chemotherapeutic agents. In addition, suberoylanilide hydroxamic acid showed synergistic anticancer activity with radiation, cisplatin, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in some cancers. Here, we report suberoylanilide hydroxamic acid also induced apoptosis in human oral cancer cells. Western blotting showed suberoylanilide hydroxamic acid increased Fas, Fas ligand, DR4, and DR5 protein expression and activated caspase-8 and caspase-9. The apoptosis was almost completely inhibited by caspase-8 inhibitor Z-IETD-FMK and attenuated by caspase-9 inhibitor Z-LEHD-FMK. Human recombinant DR5/Fc chimera protein but not Fas/Fc or DR4/Fc significantly inhibited apoptosis induced by suberoylanilide hydroxamic acid. These results suggest that suberoylanilide hydroxamic acid induces apoptosis mainly through activation of DR5/TRAIL death pathway. Furthermore, subtoxic concentrations of suberoylanilide hydroxamic acid sensitize two TRAIL resistant human oral cancer cells, SAS and Ca9-22, to exogenous recombinant TRAIL-induced apoptosis in a p53-independent manner. Combined treatment of suberoylanilide hydroxamic acid and TRAIL may be used as a new promising therapy for oral cancer.
Insights
Suberoylanilide hydroxamic acid induces apoptosis in oral cancer cells, primarily via the DR5/TRAIL pathway. This compound also sensitizes resistant cells to TRAIL, suggesting a novel therapeutic approach for oral cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Suberoylanilide hydroxamic acid (SAHA) is a promising chemotherapeutic agent inducing tumor apoptosis.
- SAHA exhibits synergistic anticancer activity with other treatments like radiation and TRAIL.
- Its effects on human oral cancer cells warrant further investigation.
Purpose of the Study:
- To investigate the mechanism of SAHA-induced apoptosis in human oral cancer cells.
- To determine if SAHA can sensitize TRAIL-resistant oral cancer cells to TRAIL therapy.
- To explore the potential of combined SAHA and TRAIL treatment for oral cancer.
Main Methods:
- Western blotting to analyze protein expression (Fas, Fas ligand, DR4, DR5) and caspase activation.
- Use of caspase inhibitors (Z-IETD-FMK, Z-LEHD-FMK) to elucidate apoptosis pathways.
- Treatment of oral cancer cells (SAS, Ca9-22) with SAHA and recombinant TRAIL.
Main Results:
- SAHA increased Fas, Fas ligand, DR4, and DR5 protein expression, activating caspase-8 and caspase-9.
- Apoptosis was primarily mediated by the DR5/TRAIL pathway, as indicated by inhibition studies.
- SAHA sensitized TRAIL-resistant oral cancer cells to TRAIL-induced apoptosis in a p53-independent manner.
Conclusions:
- SAHA induces apoptosis in human oral cancer cells mainly through the DR5/TRAIL pathway.
- SAHA can overcome TRAIL resistance in oral cancer cells.
- Combined SAHA and TRAIL therapy presents a promising new treatment strategy for oral cancer.
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