Abstract
BackgroundChemoresistance remains a critical event that accounts for colorectal cancer (CRC) lethality. The aim of this study is to explore the ability of dichloroacetate (DCA) to increase chemosensitivity in CRC and the molecular mechanisms involved.MethodsThe effects of combination treatment of DCA and oxaliplatin (L-OHP) were analysed both in vitro and in vivo. The DCA-responsive proteins in AMPK pathway were enriched using proteomic profiling technology. The effect of DCA on CAB39–AMPK signal pathway was analysed. In addition, miRNA expression profiles after DCA treatment were determined. The DCA-responsive miRNAs that target CAB39 were assayed. Alterations of CAB39 and miR-107 expression were performed both in vitro and on xenograft models to identify miR-107 that targets CAB39–AMPK–mTOR signalling pathway.ResultsDCA increased L-OHP chemosensitivity both in vivo and in vitro. DCA could upregulate CAB39 expression, which activates the AMPK/mTOR signalling pathway. CAB39 was confirmed to be a direct target of miR-107 regulated by DCA. Alterations of miR-107 expression were correlated with chemoresistance development in CRC both in vitro and in vivo.ConclusionThese findings suggest that the miR-107 induces chemoresistance through CAB39–AMPK–mTOR pathway in CRC cells, thus providing a promising target for overcoming chemoresistance in CRC.
Highlights
Colorectal cancer (CRC) is the third most commonly diagnosed cancer in males and the fourth most common cancer in females; it is the second leading cause of cancer death (9.2% of all the cancer deaths) according to the Global Cancer Statistics for 2018.1 a growing number of targeted drugs have become available to treat metastatic colorectal cancer, the 5-year relative survival rate for patients with CRC is only 65%
We found that a novel miR-107/Calcium-binding protein 39 (CAB39)/ AMPK/mTOR signalling axis regulates L-OHP resistance in CRC cells, and that DCA can effectively increase L-OHP sensitivity partly through this signalling pathway, which may aid in the design of optimal chemotherapy strategies to increase the treatment efficacy for CRC (Fig. 6f)
Studies have shown that AMPK is a negative regulator of tumour cell proliferation;[24,25] for example, AMPK pathway activation can inhibit the growth of tumour cells and promote their sensitivity to chemotherapy drugs.[7,26]
Summary
Colorectal cancer (CRC) is the third most commonly diagnosed cancer in males and the fourth most common cancer in females; it is the second leading cause of cancer death (9.2% of all the cancer deaths) according to the Global Cancer Statistics for 2018.1 a growing number of targeted drugs have become available to treat metastatic colorectal cancer, the 5-year relative survival rate for patients with CRC is only 65%. Chemotherapy remains the main treatment for stage IV cancers.[2] elucidating the mechanisms of chemoresistance and seeking new optimal clinical strategies are urgently needed. The development of specific small molecules targeting cancer metabolism has become a potential strategy. METHODS: The effects of combination treatment of DCA and oxaliplatin (L-OHP) were analysed both in vitro and in vivo. Alterations of CAB39 and miR-107 expression were performed both in vitro and on xenograft models to identify miR-107 that targets CAB39–AMPK–mTOR signalling pathway. DCA could upregulate CAB39 expression, which activates the AMPK/mTOR signalling pathway. Alterations of miR-107 expression were correlated with chemoresistance development in CRC both in vitro and in vivo. CONCLUSION: These findings suggest that the miR-107 induces chemoresistance through CAB39–AMPK–mTOR pathway in CRC cells, providing a promising target for overcoming chemoresistance in CRC
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
