Dacarbazine Resistance in Melanoma Is Driven by Cell Cycle Dysregulation Stemming from Altered Cyclin D1, GSK-3β, and p21 Expression

BACKGROUND/AIM: The overall response rate of patients with advanced metastatic melanoma treated with anticancer agents remains poor, and their prognosis is extremely unfavorable. Combination therapy has become a prevalent treatment strategy, but resistance to the key drug dacarbazine (DTIC) contributes significantly to poor outcomes. We focused on programmed cell death 4 (Pdcd4), a tumor suppressor gene, as a potential target for overcoming drug resistance. Recent studies indicate that Pdcd4 expression impacts cell cycle regulation, with its specific function varying with cancer type. To date, detailed mechanisms remain unclear. MATERIALS AND METHODS: We established DTIC-resistant mouse melanoma cells and evaluated whether resistance was acquired by measuring the proliferation of those cells. To evaluate the resistance mechanism, we investigated cell cycle regulatory factors using western blotting and flow cytometry. We also examined the relationship between Pdcd4 expression and cell cycle regulation. RESULTS: phase regulator) and Cyclin E (involved in S-phase progression) was significantly increased. Expression of p21, a CDK inhibitor, also increased. Flow cytometric analysis revealed that DTIC treatment reduces the S-phase population in non-resistant cells, but not in resistant cells, and Cyclin D1 expression remains elevated in resistant cells even after extended culture in the absence of DTIC. CONCLUSION: Pdcd4 expression is downregulated in highly malignant DTIC-resistant melanoma cells and the resulting disruption in cell cycle control may contribute to drug resistance. Reactivating Pdcd4 to modulate cell cycle progression may offer a promising approach for overcoming chemotherapy resistance in patients with tumors.