RESUMEN
Although Taxol has improved the survival of cancer patients as a first-line chemotherapeutic agent, an increasing number of patients develop resistance to Taxol after prolonged treatment. The potential mechanisms of cancer cell resistance to Taxol are not completely clear. It has been reported that microRNAs (miRNAs) are involved in regulating the sensitivity of cancer cells to various chemotherapeutic agents. In this study, we aimed to explore the role of miR-129-5p in regulating the sensitivity of breast cancer cells to Taxol. Cell apoptosis and autophagy, and the sensitivity of MCF-7 cells to Taxol were assessed with a series of in vitro assays. Our results showed that the inhibition of autophagy increased the Taxol-induced apoptosis and the sensitivity of MCF-7 cells to Taxol. Up-regulation of miR-129-5p also inhibited autophagy and induced apoptosis. Furthermore, miR-129-5p overexpression increased the sensitivity of MCF-7 cells to Taxol. High mobility group box 1 (HMGB1), a target gene of miR-129-5p and a regulator of autophagy, was negatively regulated by miR-129-5p. We found that interference of HMGB1 enhanced the chemosensitivity of Taxol by inhibiting autophagy and inducing apoptosis in MCF-7 cells. Taken together, our findings suggested that miR-129-5p increased the chemosensitivity of MCF-7 cells to Taxol through suppressing autophagy and enhancing apoptosis by inhibiting HMGB1. Using miR-129-5p/HMGB1/autophagy-based therapeutic strategies may be a potential treatment for overcoming Taxol resistance in breast cancer.
Asunto(s)
Humanos , Femenino , Neoplasias de la Mama/metabolismo , Paclitaxel/metabolismo , Proteína HMGB1/metabolismo , MicroARNs/metabolismo , Células MCF-7/metabolismo , Antineoplásicos Fitogénicos/metabolismo , Autofagia/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/tratamiento farmacológico , Regulación Neoplásica de la Expresión Génica/genética , Regulación hacia Arriba/genética , Paclitaxel/uso terapéutico , Apoptosis/genética , Resistencia a Antineoplásicos/genética , Proteína HMGB1/genética , MicroARNs/genética , Antineoplásicos Fitogénicos/uso terapéuticoRESUMEN
Present study was aimed at finding a better alternative to paclitaxel, an anticancer chemotherapeutic drug. Two targets, tubulin -1 chain and apoptosis regulator Bcl-2 protein (2O2F) were used in the study. Of these, structure of tubulin -1 chain is not known and that of Bcl-2 was taken from protein data bank with ID 2O2F. Tertiary structure model of tubulin -1 chain was predicted and validated. The validated 3D structure of tubulin -1 chain and Bcl-2 protein was taken to study their interaction with paclitaxel. Molecular docking of paclitaxel and its analogues was performed with these targets separately. Results showed that out of 84 analogues taken from PubChem, CID_44322802 had glide score of -9.62, as compared to -5.86 of paclitaxel with tubulin -1 chain. It was also observed that CID_ 9919057 had glide score of -9.0, as compared to -8.24 of paclitaxel with Bcl-2 protein. However, further experimental and clinical verification is needed to establish these analogues as drug.