OBJECTIVE To investigate the mechanism of reversal of drug resistance in triple negative breast cancer (TNBC) by Zhuidu Formula from the perspective of c-JUN-regulated glycosylation.
METHODS MTT was used to detect cell proliferation. Western blot was used to detect the expression of c-JUN, β3GnT8, ppGalNAc-T1/2, CD147, and the drug resistance proteins BCRP and MDR1. MDA-MB-231/ADR cells overexpressing c-JUN were established using transfected c-JUN plasmids. In vivo experiments were performed by in situ transplantation of drug-resistant TNBC into nude mice.
RESULTS Zhuidu Formula can significantly inhibit the proliferation of MDA-MB-231/ADR cells (P < 0.01), with a time-effect and dose-effect relationship. It also significantly inhibited the tumor weight of drug-resistant TNBC transplanted nude mice in situ (P < 0.01), reduced the expression of drug-resistant proteins BCRP and MDR1 (P < 0.01), and significantly decreased the expression of c-JUN, β3GnT8, ppGalNAc-T1/2, CD147 proteins (P < 0.01). After overexpression of c-JUN, the expression of β3GnT8, ppGalNAc T1/2, CD147, BCRP and MDR1 all showed an increase compared with the blank plasmid control group (P < 0.05, P < 0.01). The blank plasmid had no effect on the expression of the above proteins (compared with the blank control group, P > 0.05). Zhuidu Formula can significantly reduce the expression of the above proteins after overexpressing c-JUN, but the expression levels were still significantly higher than those in the blank plasmid group (P < 0.05, P < 0.01).
CONCLUSION By acting on the regulatory factor c-JUN, Zhuidu Formula down-regulated the activation of β3GnT8 and ppGalNAc-T1/2, thereby inhibiting the glycosylation modification of CD147 and leading to the down-regulation of drug-resistant proteins BCRP and MDR1 to reverse TNBC drug resistance.
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