Nuclear PKM2 contributes to gefitinib resistance via upregulation of STAT3 activation in colorectal cancer.
Nuclear PKM2 contributes to gefitinib resistance via upregulation of STAT3 activation in colorectal cancer.
复制标题
核 PKM2 通过上调结直肠癌中 STAT3 的激活而导致吉非替尼耐药。
DOI：
10.1038/srep16082
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发表时间：
2015-11-06
影响因子：
4.6
通讯作者：
Li M
中科院分区：
文献类型：
--
作者：
Li Q;Zhang D;Chen X;He L;Li T;Xu X;Li M
吉非替尼（易瑞沙，ZD-1839）是一种表皮生长因子受体（EGFR）途径的小分子酪氨酸激酶抑制剂（TKI），目前正在研究用于治疗结直肠癌（CRC）的临床试验。然而，正如所知，一些患者对TKI产生耐药性，并且在CRC中介导对EGFR-TKI的内在耐药性的机制尚未完全表征。据报道，对EGFR抑制剂的耐药性涉及神经胶质瘤和肺癌中信号转导子和转录激活子3（STAT 3）的激活。在这里，我们证明了核丙酮酸激酶亚型M2（PKM 2）水平与结直肠癌细胞中吉非替尼耐药呈正相关。核PKM 2在HT 29细胞中的过表达降低了吉非替尼治疗的效果，而PKM 2敲低增加了吉非替尼的疗效。此外，核PKM 2激活STAT 3与吉非替尼耐药相关。STAT 3特异性抑制剂Stattic或STAT 3特异性siRNA对STAT 3的抑制使耐药细胞对吉非替尼敏感。这些结果表明，核PKM 2调节CRC细胞对吉非替尼的敏感性，并表明小分子药理学破坏核PKM 2与STAT 3的结合是克服CRC患者中EGFR-TKI抗性的潜在途径。
Gefitinib (Iressa, ZD-1839), a small molecule tyrosine kinase inhibitor (TKI) of the epidermal growth factor receptor (EGFR) pathway, is currently under investigation in clinical trials for the treatment of colorectal cancer (CRC). However, as known, some patients develop resistance to TKIs, and the mechanisms mediating intrinsic resistance to EGFR-TKIs in CRC have not been fully characterized. Resistance to EGFR inhibitors reportedly involves activation of signal transducer and activator of transcription 3 (STAT3) in glioma and lung cancer. Here, we demonstrated that the nuclear pyruvate kinase isoform M2 (PKM2) levels were positively correlated with gefitinib resistance in CRC cells. The overexpression of nuclear PKM2 in HT29 cells decreased the effect of gefitinib therapy, whereas PKM2 knockdown increased gefitinib efficacy. Furthermore, the activation of STAT3 by nuclear PKM2 was associated with gefitinib resistance. Inhibition of STAT3 by Stattic, a STAT3-specific inhibitor, or STAT3-specific siRNA sensitized resistant cells to gefitinib. These results suggest that nuclear PKM2 modulates the sensitivity of CRC cells to gefitinib and indicate that small molecule pharmacological disruption of nuclear PKM2 association with STAT3 is a potential avenue for overcoming EGFR-TKI resistance in CRC patients.