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Updated: Jun 28, 2026

Unveiling Therapeutic Opportunities with Melanoma Patient-derived Organoid Models
Published on: September 6, 2024
Apoptosis induced by synthetic retinoic acid CD437 on human melanoma A375 cells involves RIG-I pathway
Min Pan1, Songmei Geng, Shengxiang Xiao
1Department of Dermatology, Affiliated Hospital of Qingdao University Medical College, 16 Jiangsu Road, 266003, Qingdao, Shandong, People's Republic of China.
Abstract:
Human malignant melanoma is notoriously resistant to currently available pharmacological modulation. Our aim was to evaluate the anti-tumor effect of a novel synthetic retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carbo-xylic acid (CD437) on melanoma cell line A375. Analysis of cell morphology showed that CD437 promoted marked apoptosis in A375 cells. To explore the mechanisms of CD437-induced apoptosis, an NF-kappaB-luciferase reporter assay was performed, demonstrating that apoptosis induction by CD437 required activation of transcription factor NF-kappaB. Importantly, based on the findings that RIG-I (retinoic acid inducible gene I) can be induced by retinotic acid and can activate NF-kappaB through a CARD-containing adaptor protein VISA, we proposed a hypothesis that RIG-I was involved in the signal pathway of NF-kappaB activation induced by CD437 through the adaptor protein VISA. By specially cleaving VISA with hepatitis C virus (HCV) non-structural (NS)3/4A, the RIG-I pathway was blocked, with subsequent simultaneous inhibition of CD437-induced NF-kappaB activation and cell apoptosis in A375 cells. These results support our hypothesis and suggest that RIG-I may be a useful intermediate biologic marker for retinoid chemoprevention and treatment studies.
Insights
The synthetic retinoid CD437 induces apoptosis in melanoma cells by activating the NF-kappaB pathway, involving RIG-I and VISA. This discovery offers potential for new melanoma treatments.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Human malignant melanoma exhibits significant resistance to current pharmacological treatments.
- Retinoids are a class of compounds with potential anti-cancer properties.
- Understanding the molecular mechanisms of retinoid action is crucial for developing effective therapies.
Purpose of the Study:
- To evaluate the anti-tumor effects of the synthetic retinoid CD437 on the A375 human melanoma cell line.
- To elucidate the molecular pathways involved in CD437-induced apoptosis.
- To investigate the role of RIG-I (retinoic acid inducible gene I) and VISA in CD437's mechanism of action.
Main Methods:
- Cell morphology analysis to assess apoptosis.
- NF-kappaB-luciferase reporter assay to measure transcription factor activation.
- Inhibition of the RIG-I pathway using hepatitis C virus (HCV) non-structural (NS)3/4A to cleave VISA.
Main Results:
- CD437 treatment induced significant apoptosis in A375 melanoma cells.
- Apoptosis induction by CD437 was dependent on the activation of the NF-kappaB transcription factor.
- Blocking the RIG-I pathway via VISA cleavage inhibited CD437-induced NF-kappaB activation and apoptosis.
Conclusions:
- CD437 demonstrates anti-tumor activity against melanoma by promoting apoptosis.
- The RIG-I-VISA-NF-kappaB signaling axis is critical for CD437's anti-melanoma effects.
- RIG-I may serve as a valuable biomarker in retinoid-based cancer chemoprevention and treatment strategies.
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