β-Sitosterol Reverses Multidrug Resistance via BCRP Suppression by Inhibiting the p53-MDM2 Interaction in Colorectal Cancer
β-Sitosterol Reverses Multidrug Resistance via BCRP Suppression by Inhibiting the p53-MDM2 Interaction in Colorectal Cancer
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DOI：
10.1021/acs.jafc.0c00107
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发表时间：
2020-03-25
影响因子：
6.1
通讯作者：
Xu, Ke
中科院分区：
文献类型：
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作者：
Wang, Ziyuan;Zhan, Yueping;Xu, Ke
植物甾醇广泛存在于植物油、坚果、谷类产品、水果和浆果中。植物甾醇诱导的治疗敏感性最近揭示了在癌症治疗中缓解多药耐药的重要性。在这里，我们证明了β-谷甾醇，最常见的饮食植物甾醇，通过抑制乳腺癌耐药蛋白(BCRP)的表达，恢复了耐药结直肠癌(CRC)细胞对奥沙利铂(OXA)的敏感性。我们进一步证明，β-谷甾醇可以通过破坏P53-MDM2的相互作用来激活P53，导致P53易位到细胞核的增加，并沉默核因子-kappa B(NF-kappa B)途径，这是BCRP表达所必需的。最后，在异种移植小鼠模型上，我们认为OXA和β-谷甾醇的联合应用具有协同抑制肿瘤的作用。这些结果表明，β-谷甾醇能够介导P53/NF-kappa B/BCRP信号轴，从而调节结直肠癌对化疗的反应。联合应用β-谷甾醇和氧XA可能是改善结直肠癌治疗的一种潜在方法。
Phytosterols are widely present in vegetable oils, nuts, cereal products, fruits, and berries. Phytosterol-induced treatment sensitivity has recently shed light on alleviating multidrug resistance in cancer therapy. Here, we demonstrated that beta-sitosterol, the most common dietary phytosterol, recovers oxaliplatin (OXA) sensitivity in drug-resistant colorectal cancer (CRC) cells by inhibiting breast cancer resistance protein (BCRP) expression. We further showed evidence that beta-sitosterol could activate p53 by disrupting the p53-MDM2 interaction, leading to an increase in p53 translocation to the nucleus and silencing the nuclear factor-kappa B (NF-kappa B) pathway, which is necessary for BCRP expression. Finally, we suggested that the combination of OXA and beta-sitosterol has a synergistic tumor suppression effect in vivo using a xenograft mouse model. These results revealed that beta-sitosterol is able to mediate the p53/NF-kappa B/BCRP signaling axis to regulate the response of CRC to chemotherapy. The combined application of beta-sitosterol and OXA can be a potential way to improve CRC treatment.