Zhao Liang, Bin Shi, He Hong-Liang, Yang Jing-Mo, Pu Yue-Chen, Gao Cai-Hong, Wang Hao, Wang Bao-Long
Department of Clinical Laboratory.
Anorectal Department of Traditional Chinese Medicine.
Anticancer Drugs. 2018 Mar;29(3):227-233. doi: 10.1097/CAD.0000000000000588.
As a new type of anticancer drug, the effect of histone deacetylase inhibitors (HDACIs) in cancer clinical therapy is disappointing owing to drug resistance. P-glycoprotein (P-gp) is clearly recognized as a multidrug resistance protein. However, the relationship between P-gp and sodium butyrate (SB), a kind of HDACIs, has not been investigated. In this study, we found that SB increased mRNA and protein expression of P-gp in lung cancer cells and the underlying mechanisms were elucidated. We found that SB treatment enhanced the mRNA and protein expression of STAT3 rather than that of β-catenin, Foxo3a, PXR, or CAR, which were reported to directly regulate the transcription of ABCB1, a P-gp-encoding gene. Interestingly, inhibition of STAT3 expression obviously attenuated SB-increased P-gp expression in lung cancer cells, indicating that STAT3 played an important role in SB-mediated P-gp upregulation. Furthermore, we found that SB increased the mRNA stability of ABCB1. In summary, this study showed that SB increased P-gp expression by facilitating transcriptional activation and improving ABCB1 mRNA stability. This study indicated that we should pay more attention to HDACIs during cancer clinical therapy.
作为一种新型抗癌药物，由于耐药性，组蛋白脱乙酰酶抑制剂（HDACIs）在癌症临床治疗中的效果令人失望。P-糖蛋白（P-gp）被明确认为是一种多药耐药蛋白。然而，P-gp与一种HDACIs——丁酸钠（SB）之间的关系尚未得到研究。在本研究中，我们发现SB可增加肺癌细胞中P-gp的mRNA和蛋白表达，并阐明了其潜在机制。我们发现SB处理增强了STAT3的mRNA和蛋白表达，而非β-连环蛋白、Foxo3a、PXR或CAR的表达，据报道这些蛋白可直接调节P-gp编码基因ABCB1的转录。有趣的是，抑制STAT3表达明显减弱了SB诱导的肺癌细胞中P-gp表达增加，表明STAT3在SB介导的P-gp上调中起重要作用。此外，我们发现SB增加了ABCB1的mRNA稳定性。总之，本研究表明SB通过促进转录激活和提高ABCB1 mRNA稳定性来增加P-gp表达。本研究表明，在癌症临床治疗期间我们应更加关注HDACIs。
