Zhang Yang, Talmon G, Wang J
1] Eppley Institute for Research in Cancer and Allied Diseases, 985950 Nebraska Medical Center, Omaha, NE 68198, USA [2] Department of Genetics, Cell Biology and Anatomy, 985950 Nebraska Medical Center, Omaha, NE 68198, USA.
Department of Pathology and Microbiology, University of Nebraska Medical Center, 985950 Nebraska Medical Center, Omaha, NE 68198, USA.
Cell Death Dis. 2015 Aug 6;6(8):e1845. doi: 10.1038/cddis.2015.200.
Drug resistance is one of the major hurdles for cancer treatment. However, the underlying mechanisms are still largely unknown and therapeutic options remain limited. In this study, we show that microRNA (miR)-587 confers resistance to 5-fluorouracil (5-FU)-induced apoptosis in vitro and reduces the potency of 5-FU in the inhibition of tumor growth in a mouse xenograft model in vivo. Further studies indicate that miR-587 modulates drug resistance through downregulation of expression of PPP2R1B, a regulatory subunit of the PP2A complex, which negatively regulates AKT activation. Knockdown of PPP2R1B expression increases AKT phosphorylation, which leads to elevated XIAP expression and enhanced 5-FU resistance; whereas rescue of PPP2R1B expression in miR-587-expressing cells decreases AKT phosphorylation/XIAP expression, re-sensitizing colon cancer cells to 5-FU-induced apoptosis. Moreover, a specific and potent AKT inhibitor, MK2206, reverses miR-587-conferred 5-FU resistance. Importantly, studies of colorectal cancer specimens indicate that the expression of miR-587 and PPP2R1B positively and inversely correlates with chemoresistance, respectively, in colorectal cancer. These findings indicate that the miR-587/PPP2R1B/pAKT/XIAP signaling axis has an important role in mediating response to chemotherapy in colorectal cancer. A major implication of our study is that inhibition of miR-587 or restoration of PPP2R1B expression may have significant therapeutic potential to overcome drug resistance in colorectal cancer patients and that the combined use of an AKT inhibitor with 5-FU may increase efficacy in colorectal cancer treatment.
耐药性是癌症治疗的主要障碍之一。然而，其潜在机制仍 largely unknown 且治疗选择仍然有限。在本研究中，我们表明微小 RNA（miR）-587 在体外赋予对 5-氟尿嘧啶（5-FU）诱导的细胞凋亡的抗性，并在体内小鼠异种移植模型中降低 5-FU 抑制肿瘤生长的效力。进一步的研究表明，miR-587 通过下调 PP2A 复合物的调节亚基 PPP2R1B 的表达来调节耐药性，PP2A 复合物负调节 AKT 激活。敲低 PPP2R1B 的表达会增加 AKT 磷酸化，导致 XIAP 表达升高并增强 5-FU 抗性；而在表达 miR-587 的细胞中恢复 PPP2R1B 的表达会降低 AKT 磷酸化/XIAP 表达，使结肠癌细胞对 5-FU 诱导的细胞凋亡重新敏感。此外，一种特异性且有效的 AKT 抑制剂 MK2206 可逆转 miR-587 赋予的 5-FU 抗性。重要的是，对结直肠癌标本的研究表明，miR-587 和 PPP2R1B 的表达分别与结直肠癌的化疗耐药性呈正相关和负相关。这些发现表明，miR-587/PPP2R1B/pAKT/XIAP 信号轴在介导结直肠癌对化疗的反应中起重要作用。我们研究的一个主要意义是，抑制 miR-587 或恢复 PPP2R1B 的表达可能具有克服结直肠癌患者耐药性的显著治疗潜力，并且将 AKT 抑制剂与 5-FU 联合使用可能会提高结直肠癌治疗的疗效。
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