2'-Hydroxy-4-methylsulfonylchalcone enhances TRAIL-induced apoptosis in prostate cancer cells
Bassel Ismail1, Catherine Fagnere, Youness Limami
1aBiochemistry and Molecular Biology Laboratory bOrganic Chemistry and Therapeutic Laboratory cBiophysical Laboratory, Faculty of Pharmacy, University of Limoges, FR 3503 GEIST, EA1069, GDR CNRS 3049 dPlate-forme CIM, University of Limoges, Limoges, France eBiochemistry Department, Faculty of Science - Section II, Lebanese University, TM-PAC Team, Jdeidet, Lebanon.
Abstract:
Prostate cancer is the most common malignant cancer in men and the second leading cause of cancer deaths. Previously, we have shown that 2'-hydroxy-4-methylsulfonylchalcone (RG003) induced apoptosis in prostate cancer cell lines PC-3 and DU145. Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent, some cancer cells are resistant to TRAIL treatment. PC-3 and LNCaP prostatic cancer cell lines have been reported to be resistant to TRAIL-induced apoptosis. Here, we show for the first time that RG003 overcomes TRAIL resistance in prostate cancer cells. RG003 can enhance TRAIL-induced apoptosis through DR5 upregulation and downregulation of Bcl-2, PI3K/Akt, NF-κB, and cyclooxygenase-2 (COX-2) survival pathways. When used in combined treatment, RG003 and TRAIL amplified TRAIL-induced activation of apoptosis effectors and particularly activation of caspase-8 and the executioner caspase-3, leading to increased poly-ADP-ribose polymerase cleavage and DNA fragmentation in prostate cancer cells. Furthermore, we showed that RG003 reduced COX-2 expression in cells. Previously, we showed that COX-2 was involved in resistance to an apoptosis mechanism; then, its inhibition by RG003 could render cells more sensitive to TRAIL treatment. We showed that nuclear factor-κB activation was inhibited after RG003 treatment. This inhibition was correlated with reduction in COX-2 expression and induction of apoptosis. Overall, we conclude, for the first time, that RG003 can enhance TRAIL-induced apoptosis in human prostate cancer cells. The significance of our in-vitro study with RG003 and TRAIL combined is very encouraging, suggesting the relevance of testing this combined treatment in xenograft animal models.
Insights
This study shows that 2'-hydroxy-4-methylsulfonylchalcone (RG003) can overcome resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in prostate cancer cells. Combined treatment with RG003 and TRAIL enhances apoptosis induction, offering a promising therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Prostate cancer is a leading cause of cancer death in men.
- Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) shows potential as an anticancer agent but faces resistance issues in some cancer cells.
- Previous research demonstrated RG003's ability to induce apoptosis in specific prostate cancer cell lines.
Purpose of the Study:
- To investigate the efficacy of RG003 in overcoming TRAIL resistance in prostate cancer.
- To elucidate the molecular mechanisms by which RG003 enhances TRAIL-induced apoptosis.
- To evaluate the combined therapeutic potential of RG003 and TRAIL against prostate cancer.
Main Methods:
- Utilized prostate cancer cell lines (PC-3, DU145, LNCaP) known for TRAIL resistance.
- Assessed apoptosis induction via caspase activation, PARP cleavage, and DNA fragmentation.
- Investigated the modulation of key survival pathways including DR5, Bcl-2, PI3K/Akt, NF-κB, and COX-2.
Main Results:
- RG003 effectively overcomes TRAIL resistance in prostate cancer cells.
- Combined RG003 and TRAIL treatment significantly enhances apoptosis by upregulating DR5 and downregulating Bcl-2, PI3K/Akt, NF-κB, and COX-2.
- RG003 inhibits nuclear factor-κB (NF-κB) activation and reduces cyclooxygenase-2 (COX-2) expression, contributing to increased sensitivity to TRAIL.
Conclusions:
- RG003 enhances TRAIL-induced apoptosis in human prostate cancer cells, marking a significant advancement.
- The combined RG003 and TRAIL treatment demonstrates a promising synergistic effect, warranting further investigation.
- This in-vitro study suggests the potential of combined RG003 and TRAIL therapy for prostate cancer treatment, supporting future xenograft model studies.
