GSK-3 inhibitor induces apoptosis and cell cycle arrest in CD133+/CD44+ prostate cancer cells through modulation of Notch signaling pathway.

BACKGROUND: Treatment of advanced prostate cancer (PCa) is a major challenge due to the persistence of drug-resistant cancer stem cells (CSCs), which are mainly responsible for metastasis and recurrence. Therefore, the key to achieve an effective treatment approach in PCa is through the development of strategies targeting CSCs. GSK-3, also known as a moonlight kinase, is associated with multiple signaling pathways involved in embryonic development and cancer, including Wnt/β-catenin, Sonic hedgehog, and Notch. Strong evidence suggests that pharmacological inhibition of GSK-3 can eliminate the prostate cancer stem/progenitor-like population. The present study aims to evaluate the effects of GSK-3 inhibitor IX on CD133+/CD44+ cells isolated from DU145 cell line.

METHODS AND RESULTS: Following treatment with various concentrations of GSK-3 inhibitor IX, we assessed cell viability, apoptosis, cell cycle, and multicellular tumor spheroids formation capacity. Furthermore, expression levels of components in the Notch signaling pathway due to GSK-3 inhibition were examined by immunofluorescence staining. The results revealed that GSK-3 inhibitor IX exhibited strong anti-proliferative effects by inducing apoptotic cell death, causing G0/G1 phase arrest of CD133+/CD44+ cells. The number and size of the spheroids decreased significantly upon treatment with GSK-3 inhibitor IX. Furthermore, GSK-3 inhibition resulted in a marked reduction in the expression of Notch1 and Delta, which are important components of the Notch signaling pathway.

CONCLUSION: Together, our data demonstrated that GSK-3 inhibitor IX effectively eliminated CD133+/CD44+ cells by suppressing the Notch signaling pathway, which is critical for CSC maintenance and survival, and may offer a promising therapeutic strategy for prostate cancer treatment with further research.