Transcriptome and Proteome Analysis Reveals Corosolic Acid Inhibiting Bladder Cancer via Targeting Cell Cycle and Inducing Mitophagy in Vitro and in Vivo

Abstract Background Existing chemotherapy and radiotherapy methods have drawbacks such as high toxicity, high side effects, poor efficacy, and chemoresistance. Therefore, there is an urgent need to develop new anti-cancer drugs with low toxicity and high efficiency for cancer therapy and the prevention of recurrence. Corosolic acid (CA) is a medicine and food homologue and has many biological activities of health care. However, the anti-tumor effects and mechanism of CA in bladder cancer remain unexplored. Methods To study the anticancer effect of CA on bladder cancer cells, CCK8, EdU, high-content living cell imaging experiments were performed. And the mice model was used to verify the anticancer effect and toxicity for mice. To investigate the molecular mechanism of CA inhibition on bladder cancer cells, transcriptomics and proteomics were employed. To further verify the pharmacological mechanism, flow cytometry, RT-qPCR, western blotting and immunofluorescence staining experiments were performed, and the CA targeting molecules were analyzed in combination with our experimental and public clinical data. Results We found that CA inhibited bladder cancer cell proliferation in a concentration- and time-dependent manner. Xenograft experiments showed that CA inhibited the growth of subcutaneous tumors, and had no toxicity in mice. Integration of omics analysis revealed that low concentrations of CA inhibited bladder cancer cells proliferation via attenuating DNA synthesis by downregulating TOP2A and LIG1, and via diminishing mitosis by downregulating CCNA2, CCNB1, CDC20, and RRM2. High concentrations of CA induced cell death not through the apoptotic pathway but through triggering mitophagy pathway via upregulating SQSTM1/P62, NBR1, and UBB. Conclusions CA, a natural compound homologous to medicine and food, inhibits the mitosis of bladder cancer cells at low concentrations, and kills bladder cancer cells by inducing mitophagy at high concentrations. This study provides a comprehensive understanding of the pharmacological mechanism of CA inhibition in bladder cancer for the first time, which is helpful for the development of new anti-tumor drugs based on CA.