Curcumin Analog GO-Y030 Triggers JNK and p38 Signalling to Activate Apoptotic Cascades in Human Osteosarcoma Cells
Yu-Hsien Lin1,2, Jia-Sin Yang1,3, Chia-Hsuan Chou1,3
1Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
Abstract:
Osteosarcoma, the most common primary bone cancer in adolescents, often carries a grim prognosis due to its high metastatic potential. Due to its low bioavailability, curcumin limits its adjuvant efficacy in improving prognosis and long-term survival in osteosarcoma patients. To investigate apoptosis induced by the synthesised curcumin analog GO-Y030 in human osteosarcoma cells, flow cytometry, annexin V-fluorescein isothiocyanate-labelled/propidium iodide staining, human apoptosis array, and Western blotting were used. GO-Y030 dose-dependently reduced viability and induced sub-G1 arrest and apoptosis in human osteosarcoma U2OS and 143B cells. GO-Y030 significantly activated caspases 8, 9, and 3, while suppressing cellular inhibitors of apoptosis protein 1 (cIAP-1) and X-chromosome-linked IAP. GO-Y030 increased the phosphorylation of extracellular signal-regulated protein kinases (ERK)1/2, c-Jun N-terminal kinases (JNK)1/2, and p38. Inhibitors of JNK (JNK-IN-8) and p38 (SB203580) suppressed GO-Y030-induced cleavage of caspases 8, 9, and 3, whereas co-treatment with the ERK inhibitor (U0126) did not lessen their activation. Overall, GO-Y030 triggers both extrinsic and intrinsic apoptotic cascades in U2OS and 143B cells by activating the JNK1/2 and p38 pathways, shedding light on its mechanism of action against human osteosarcoma cells.
Insights
A novel curcumin analog, GO-Y030, effectively induces apoptosis in human osteosarcoma cells by activating key cell death pathways. This research offers new therapeutic strategies for osteosarcoma treatment.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Osteosarcoma is a primary bone cancer with high metastatic potential, particularly in adolescents.
- Curcumin's low bioavailability limits its effectiveness as an adjuvant therapy for osteosarcoma.
- There is a need for novel therapeutic agents to improve outcomes for osteosarcoma patients.
Purpose of the Study:
- To investigate the apoptosis-inducing effects of the synthesized curcumin analog GO-Y030 in human osteosarcoma cells.
- To elucidate the molecular mechanisms underlying GO-Y030's action against osteosarcoma.
- To assess GO-Y030's potential as a therapeutic agent for osteosarcoma.
Main Methods:
- Flow cytometry and Annexin V/propidium iodide staining were used to assess apoptosis.
- Human apoptosis arrays and Western blotting were employed to analyze protein expression and activation.
- Specific pathway inhibitors (JNK, p38, ERK) were utilized to determine the role of signaling pathways.
Main Results:
- GO-Y030 dose-dependently reduced osteosarcoma cell viability and induced apoptosis.
- GO-Y030 activated caspases 8, 9, and 3, and modulated inhibitor of apoptosis proteins (IAPs).
- GO-Y030 increased phosphorylation of JNK1/2 and p38, which were crucial for GO-Y030-induced apoptosis, while ERK activation was not essential.
Conclusions:
- GO-Y030 effectively triggers both extrinsic and intrinsic apoptotic pathways in human osteosarcoma cells.
- The JNK1/2 and p38 signaling pathways are critical mediators of GO-Y030's anti-osteosarcoma activity.
- GO-Y030 demonstrates significant potential as a therapeutic agent for osteosarcoma.
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