8-Br-cGMP activates HSPB6 and increases the antineoplastic activity of quinidine in prostate cancer.

Heat shock protein family B [small] member 6 (HSPB6), widely found in various muscles, has been recently identified as a tumor suppressor gene. However, its role in prostate cancer remains unexplored. Herein, we investigated the expression of HSPB6 in prostate cancer and its association with prognosis. Our findings revealed that HSPB6 downregulation in prostate cancer correlated with a poor prognosis. Moreover, we discovered that HSPB6 can be phosphorylated and activated by 8-Br-cGMP, leading to apoptosis in prostate cancer cells by activating Cofilin. Additionally, we demonstrated that knocking down E2F1 by quinidine administration enhances the transcriptional level of HSPB6. Furthermore, we evaluated the combination of quinidine and 8-Br-cGMP as a potential therapeutic strategy for prostate cancer. Our results revealed that the combined treatment was more effective than either treatment alone in inhibiting the growth of prostate cancer through the HSPB6 pathway, both in vitro and in vivo. Overall, our study provides compelling evidence that HSPB6 suppresses malignant behavior in prostate cancer by inducing apoptosis. The combination of quinidine and 8-Br-cGMP emerges as a promising approach for the treatment of prostate cancer.

PDE3B regulates KRT6B and increases the sensitivity of bladder cancer cells to copper ionophores.

Cuproptosis is a new Cu-dependent programmed cell death manner that has shown regulatory functions in many tumor types, however, its mechanism in bladder cancer remains unclear. Here, we reveal that Phosphodiesterase 3B (PDE3B), a cuproptosis-associated gene, could reduce the invasion and migration of bladder cancer. PDE3B is downregulated in bladder cancer tissues, which is correlated with better prognosis. Conversely, overexpression of PDE3B in bladder cancer cell could significantly resist invasion and migration, which is consistent with the TCGA database results. Future study demonstrate the anti-cancer effect of PDE3B is mediated by Keratin 6B (KRT6B) which leads to the keratinization. Therefore, PDE3B can reduce KRT6B expression and inhibit the invasion and migration of bladder cancer. Meanwhile, increased expression of PDE3B was able to enhance the sensitivity of Cuproptosis drug thiram. This study show that PDE3B/KRT6B is a potential cancer therapeutic target and PDE3B activation is able to increase the sensitivity of bladder cancer cells to copper ionophores.