Guan Mingxiu, Tong Yingna, Guan Minghua, Liu Xiaobin, Wang Meng, Niu Ruifang, Zhang Fei, Dong Dong, Shao Jie, Zhou Yunli
1 Department of Clinical Laboratory, Tianjin Baodi Hospital, Tianjin Baodi Affiliated Hospital of Tianjin Medical University, Baodi District, Tianjin, China.
2 Department of Clinical Laboratory, Tianjin Children's Hospital, Beichen District, Tianjin, China.
Technol Cancer Res Treat. 2018 Jan 1;17:1533034617749418. doi: 10.1177/1533034617749418.
Pyruvate kinase type M2, which is expressed in multiple tumor cell types and plays a key role in aerobic glycolysis, also has nonglycolytic functions and can regulate transcription and cell proliferation. The results of this study show that epidermal growth factor receptor activation induces pyruvate kinase type M2 nuclear translocation. To further determine the relationship between pyruvate kinase type M2 and epidermal growth factor receptor, we analyzed pathological data from mammary glands and performed epidermal growth factor receptor/human epidermal growth factor receptor 2 knockdown to reveal that pyruvate kinase type M2 is associated with epidermal growth factor receptor and human epidermal growth factor receptor 2. Lapatinib is a small molecule epidermal growth factor receptor tyrosine kinase inhibitor that can inhibit epidermal growth factor receptor and human epidermal growth factor receptor 2, though its effect on pyruvate kinase type M2 remains elusive. Accordingly, we performed Western blotting and reverse transcription polymerase chain reaction and analyzed pathological data from mammary glands, with results suggesting that lapatinib inhibits pyruvate kinase type M2 expression. We further found that the antitumor drug lapatinib inhibits breast cancer cell proliferation by influencing pyruvate kinase type M2 expression, as based on Cell Counting Kit-8 analyses and pyruvate kinase type M2 overexpression experiments. Signal transducer and activator of transcription 3, which is a transcription factor-associated cell proliferation and the only transcription factor that interacts with pyruvate kinase type M2, we performed pyruvate kinase type M2 knockdown experiments in Human breast cancer cells MDA-MB-231 and Human breast cancer cells SK-BR-3 cell lines and examined the effect on levels of Signal transducer and activator of transcription 3 and phosphorylated Signal transducer and activator of transcription 3. The results indicate that pyruvate kinase type M2 regulates Signal transducer and activator of transcription 3 and phospho-Stat3 (Tyr705) expression. Together with previous reports, our findings show that lapatinib inhibits breast cancer cell proliferation by influencing pyruvate kinase type M2 expression, which results in a reduction in both Signal transducer and activator of transcription 3 and phosphorylated Signal transducer and activator of transcription 3.
丙酮酸激酶M2型在多种肿瘤细胞类型中表达，在有氧糖酵解中起关键作用，同时也具有非糖酵解功能，能够调节转录和细胞增殖。本研究结果表明，表皮生长因子受体激活可诱导丙酮酸激酶M2型核转位。为进一步确定丙酮酸激酶M2型与表皮生长因子受体之间的关系，我们分析了乳腺的病理数据，并进行了表皮生长因子受体/人表皮生长因子受体2基因敲低实验，结果显示丙酮酸激酶M2型与表皮生长因子受体及人表皮生长因子受体2相关。拉帕替尼是一种小分子表皮生长因子受体酪氨酸激酶抑制剂，可抑制表皮生长因子受体和人表皮生长因子受体2，但其对丙酮酸激酶M2型的作用仍不明确。因此，我们进行了蛋白质免疫印迹和逆转录聚合酶链反应，并分析了乳腺的病理数据，结果表明拉帕替尼可抑制丙酮酸激酶M2型的表达。我们进一步发现，基于细胞计数试剂盒8分析和丙酮酸激酶M2型过表达实验，抗肿瘤药物拉帕替尼通过影响丙酮酸激酶M2型的表达来抑制乳腺癌细胞增殖。信号转导子和转录激活子3是一种与转录因子相关的细胞增殖因子，也是唯一与丙酮酸激酶M2型相互作用的转录因子，我们在人乳腺癌细胞MDA-MB-231和人乳腺癌细胞SK-BR-3细胞系中进行了丙酮酸激酶M2型基因敲低实验，并检测了其对信号转导子和转录激活子3及磷酸化信号转导子和转录激活子3水平的影响。结果表明，丙酮酸激酶M2型调节信号转导子和转录激活子3及磷酸化信号转导子和转录激活子3（酪氨酸705）的表达。与之前的报道一致，我们的研究结果表明，拉帕替尼通过影响丙酮酸激酶M2型的表达来抑制乳腺癌细胞增殖，进而导致信号转导子和转录激活子3及磷酸化信号转导子和转录激活子3水平降低。
