Simultaneous inhibition of atypical protein kinase-C and mTOR impedes bladder cancer cell progression

Despite enormous scientific advancements in cancer treatment, there is a need for research to combat cancer, particularly bladder cancer. Drugs once proved to be effective in treating bladder cancer have shown reduced efficacy; hence, the cancer recurrence rate is increasing. To overcome this situation, several strategies have been considered, including the development of novel active drugs or modification of existing therapeutic regimens by combining two or more existing drugs. In recent years, atypical protein kinase Cs (PKCs), phospholipid-dependent serine/threonine kinases, have been considered as a central regulator of various cancer-associated signaling pathways, and they control cell cycle progression, tumorigenesis and metastasis. Additionally, the biologically crucial mTOR signaling pathway is altered in numerous types of cancer, including bladder cancer. Furthermore, despite independent activation, atypical PKC signaling can be triggered by mTOR. The present study examined whether the concurrent inhibition of atypical PKCs and mTOR using a combination of novel atypical PKC inhibitors (ICA-I, an inhibitor of PKC-iota; or zeta-Stat, an inhibitor of PKC-zeta) and rapamycin blocks bladder cancer progression. In the present study, healthy bladder MC-SV-HUCT2 and bladder cancer TCCSUP cells were tested and subjected to a WST1 assay, western blot analysis, immunoprecipitation, a scratch wound healing assay, flow cytometry and immunofluorescence analyses. The results revealed that the combination therapy induced a reduction in human bladder cancer cell viability compared with control and individual atypical PKC inhibitor and rapamycin treatment. Additionally, the concurrent inhibition of atypical PKCs and mTOR retards the migration of bladder cancer cells. These findings indicated that the administration of atypical PKC inhibitors together with rapamycin could be a useful therapeutic option in treating bladder cancer.