Abstract
DNA repair systems are abnormally active in most hepatocellular carcinoma (HCC) cells due to accumulated mutations, resulting in elevated DNA repair capacity and resistance to chemotherapy and radiotherapy. Thus, targeting DNA repair mechanisms is a common treatment approach in HCC to sensitize cancer cells to DNA damage. In this study, we examined the anti-HCC effects of melatonin and elucidated the regulatory mechanisms. The results of functional assays showed that in addition to inhibiting the proliferation, migration, and invasion abilities of HCC cells, melatonin suppressed their DNA repair capacity, thereby promoting the cytotoxicity of chemotherapy and radiotherapy. Whole-transcriptome and gain- and loss-of-function analyses revealed that melatonin induces expression of the long noncoding RNA RAD51-AS1, which binds to RAD51 mRNA to inhibit its translation, effectively decreasing the DNA repair capacity of HCC cells and increasing their sensitivity to chemotherapy and radiotherapy. Animal models further demonstrated that a combination of melatonin and the chemotherapeutic agent etoposide (VP16) can significantly enhance tumor growth inhibition compared with monotherapy. Our results show that melatonin is a potential adjuvant treatment for chemotherapy and radiotherapy in HCC.
Highlights
Hepatocellular carcinoma (HCC) is the most common cancer of the liver and ranks fifth in global cancer incidence [1,2], with ~700,000 people worldwide being diagnosed with hepatocellular carcinoma (HCC) every year.HCC is one of the most refractory malignant tumors, especially when it has progressed to late stages and surgical resection is no longer feasible, and chemotherapy is the only treatment optionCancers 2018, 10, 320; doi:10.3390/cancers10090320 www.mdpi.com/journal/cancersCancers 2018, 10, 320 available for these patients
Recent studies have demonstrated that the effects of chemotherapy and radiotherapy can be significantly enhanced when the DNA repair pathway in cancer cells is blocked, and DNA repair blockers, such as trans-resveratrol, B02, and IBR2, have been widely used for clinical treatment to reduce the dose of chemotherapeutic drugs and improve their therapeutic effects [5,6,7]
The results revealed that melatonin can significantly inhibit the proliferation, migration, and invasion capacities of HCC cells and can synergize with chemotherapeutic agents to enhance their cytotoxic effects against HCC cells
Summary
Hepatocellular carcinoma (HCC) is the most common cancer of the liver and ranks fifth in global cancer incidence [1,2], with ~700,000 people worldwide being diagnosed with HCC every year.HCC is one of the most refractory malignant tumors, especially when it has progressed to late stages and surgical resection is no longer feasible, and chemotherapy is the only treatment optionCancers 2018, 10, 320; doi:10.3390/cancers10090320 www.mdpi.com/journal/cancersCancers 2018, 10, 320 available for these patients. Etoposide (VP16) and camptothecin (CPT), which induce DNA damage in cancer cells and result in apoptosis, are commonly used in the clinic as chemotherapeutic agents [3,4]. DNA repair systems in most HCC cells are abnormally active due to the accumulation of mutations, resulting in elevated DNA repair capacity and poor chemotherapy outcomes. Recent studies have demonstrated that the effects of chemotherapy and radiotherapy can be significantly enhanced when the DNA repair pathway in cancer cells is blocked, and DNA repair blockers, such as trans-resveratrol, B02, and IBR2, have been widely used for clinical treatment to reduce the dose of chemotherapeutic drugs and improve their therapeutic effects [5,6,7]. DNA repair mechanisms can be subdivided into two major categories: double-strand break repair (DSBR) and single-strand break repair (SSBR) [12]
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