Corylin increases the sensitivity of hepatocellular carcinoma cells to chemotherapy through long noncoding RNA RAD51-AS1-mediated inhibition of DNA repair

Cell Death & Disease, May 2018

Corylin, a biologically active agent extracted from Psoralea corylifolia L. (Fabaceae), promotes bone differentiation and inhibits inflammation. Currently, few reports have addressed the biological functions that are regulated by corylin, and to date, no studies have investigated its antitumor activity. In this study, we used cell functional assays to analyze the antitumor activity of corylin in hepatocellular carcinoma (HCC). Furthermore, whole-transcriptome assays were performed to identify the downstream genes that were regulated by corylin, and gain-of-function and loss-of-function experiments were conducted to examine the regulatory roles of the above genes. We found that corylin significantly inhibited the proliferation, migration, and invasion of HCC cells and increased the toxic effects of chemotherapeutic agents against HCC cells. These properties were due to the induction of a long noncoding RNA, RAD51-AS1, which bound to RAD51 mRNA, thereby inhibiting RAD51 protein expression, thus inhibiting the DNA damage repair ability of HCC cells. Animal experiments also showed that a combination treatment with corylin significantly increased the inhibitory effects of the chemotherapeutic agent etoposide (VP16) on tumor growth. These findings indicate that corylin has strong potential as an adjuvant drug in HCC treatment and that corylin can strengthen the therapeutic efficacy of chemotherapy and radiotherapy.

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Corylin increases the sensitivity of hepatocellular carcinoma cells to chemotherapy through long noncoding RNA RAD51-AS1-mediated inhibition of DNA repair

Abstract Corylin, a biologically active agent extracted from Psoralea corylifolia L. (Fabaceae), promotes bone differentiation and inhibits inflammation. Currently, few reports have addressed the biological functions that are regulated by corylin, and to date, no studies have investigated its antitumor activity. In this study, we used cell functional assays to analyze the antitumor activity of corylin in hepatocellular carcinoma (HCC). Furthermore, whole-transcriptome assays were performed to identify the downstream genes that were regulated by corylin, and gain-of-function and loss-of-function experiments were conducted to examine the regulatory roles of the above genes. We found that corylin significantly inhibited the proliferation, migration, and invasion of HCC cells and increased the toxic effects of chemotherapeutic agents against HCC cells. These properties were due to the induction of a long noncoding RNA, RAD51-AS1, which bound to RAD51 mRNA, thereby inhibiting RAD51 protein expression, thus inhibiting the DNA damage repair ability of HCC cells. Animal experiments also showed that a combination treatment with corylin significantly increased the inhibitory effects of the chemotherapeutic agent etoposide (VP16) on tumor growth. These findings indicate that corylin has strong potential as an adjuvant drug in HCC treatment and that corylin can strengthen the therapeutic efficacy of chemotherapy and radiotherapy. Introduction Hepatocellular carcinoma (HCC) is the most common liver cancer and is the fifth most prevalent cancer globally1. Every year, ~700,000 people worldwide receive a diagnosis of HCC2. Currently, the mainstay treatment of HCC is surgical resection, and patients with late-stage cancer and distal metastases receive chemotherapy3, 4. The latter can result in DNA damage in cancer cells and induce apoptosis. Nevertheless, mutations in the DNA repair systems of many HCC cells result in excessive activation and poor chemotherapeutic efficacy5, 6. Therefore, in clinical practice, chemotherapy is often combined with DNA repair inhibitors to increase its therapeutic efficacy7,8,9,10. The use of traditional Chinese medicine (TCM) in the treatment of diseases has a long history in China11,12,13. Compared with Western medicine, TCM provides another effective treatment option with relatively mild side effects14,15,16. In recent years, relevant studies on the use of TCM in cancer treatment have gradually attracted attention. Nevertheless, differences in the quality of TCM are caused by differences in the concentrations of natural biologically active ingredients in herbs and other substances, and this situation usually results in unstable therapeutic efficacy and limits the applications of TCM17,18,19. Therefore, to enhance and stabilize the therapeutic efficacy of TCM, many studies have focused on identifying and purifying the biologically active ingredients of the medicinal substances used in TCM18. With developments in chemical purification technologies and mass spectrometry, the active ingredients of many TCM substances have been successively purified, and their functions have been determined20,21,22,23. These extracts can be used at lower doses and can provide more specific therapeutic efficacies. Lately, many TCM-derived compounds, such as trans-resveratrol, artemisinin, and curcumin, have been tested in cancer treatment and have shown good efficacy24,25,26,27,28. Some of these drugs can significantly inhibit the growth and metastasis of HCC and significantly increase the survival times of patients29,30,31,32. In addition, many TCM extracts, such as trans-resveratrol, have the capacity to inhibit DNA damage repair, and these drugs can synergize with chemotherapy and radiotherapy to enhance their therapeutic efficacies33, 34. Psoralea corylifolia L. (Fabaceae) is an herb that is commonly used in TCM in Asian countries and has antioxidant, anti-inflammatory, and anticancer effects35,36,37,38. This herb is often used in the treatment of inflammation due to bacterial infections. Corylin is a flavonoid compound that is extracted from P. corylifolia L., and the current understanding of its effects is limited. Corylin is known to promote bone differentiation and to inhibit inflammation by suppressing inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX) expression that is induced by bacterial infection39,40,41. To date, no studies have examined the anticancer effects of corylin. In this study, we used cell and animal models to analyze the antitumor activity of corylin in HCC and to elucidate its molecular mechanisms of action. We found that corylin can inhibit DNA repair in HCC cells. This action is due to the induction of a long noncoding RNA (lncRNA) called RAD51-AS1, which binds to RAD51 mRNA and downregulates the RAD51 protein. This change increases the sensitivity of HCC cells to chemotherapy and radiotherapy. Results Corylin inhibits the proliferation, migration, and invasio (...truncated)


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Chin-Chuan Chen, Chi-Yuan Chen, Shir-Hwa Ueng, Chuen Hsueh, Chau-Ting Yeh, Jar-Yi Ho, Li-Fang Chou, Tong-Hong Wang. Corylin increases the sensitivity of hepatocellular carcinoma cells to chemotherapy through long noncoding RNA RAD51-AS1-mediated inhibition of DNA repair, Cell Death & Disease, 2018, Issue: 9, DOI: 10.1038/s41419-018-0575-0