Axl receptor tyrosine kinase is up-regulated in metformin resistant prostate cancer cells.
Axl receptor tyrosine kinase is up-regulated in metformin resistant prostate cancer cells.
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DOI：
10.18632/oncotarget.4148
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发表时间：
2015-06-20
期刊：
影响因子：
--
通讯作者：
Bertino JR
中科院分区：
文献类型：
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作者：
Bansal N;Mishra PJ;Stein M;DiPaola RS;Bertino JR
最近的流行病学研究表明，广泛使用的抗糖尿病药物二甲双胍可以预防某些癌症。二甲双胍在血液恶性肿瘤和实体癌的临床前研究中也具有抗增殖作用，并且测试二甲双胍作为抗癌药物的临床研究正在进行中。然而，并非所有癌症类型都对二甲双胍有相同的疗效或产生耐药性。为了了解获得性耐药的机制及其作为抗增殖剂的可能作用机制，我们开发了二甲双胍耐药的 LNCaP 前列腺癌细胞。与亲本细胞相比，二甲双胍耐药的LNCaP细胞增殖率增加，迁移和侵袭能力增强，并表达上皮间质转化（EMT）标志物。将抗性细胞与野生型细胞进行详细的基因表达微阵列比较显示，Edil2、Ereg、Axl、Anax2、CD44 和 Anax3 是上调最多的基因，钙结合蛋白 2 和 TPTE（具有张力蛋白同源性的跨膜磷酸酶）和 IGF1R 下调。我们重点关注 Axl，这是一种受体酪氨酸激酶，已被证明在几种耐药癌症中表达上调。在这里，我们表明，与不过度表达 Axl 的雄激素敏感的 LNCaP 和 CWR22 细胞相比，过度表达 Axl 的二甲双胍抗性细胞系以及去势抗性细胞系对二甲双胍和泰素帝更具抗性。 LNCaP 细胞中 Axl 的强制过度表达会降低二甲双胍和泰索帝的敏感性，而耐药细胞中 Axl 的敲除会增加对这些药物的敏感性。 R428（一种小分子 Axl 激酶抑制剂）对 Axl 活性的抑制使过表达 Axl 的二甲双胍耐药细胞对二甲双胍敏感。 Axl 抑制剂可能会增强过度表达 Axl 的癌症对二甲双胍和其他化疗的肿瘤反应。
Recent epidemiological studies showed that metformin, a widely used anti-diabetic drug might prevent certain cancers. Metformin also has an anti-proliferative effect in preclinical studies of both hematologic malignancies as well as solid cancers and clinical studies testing metformin as an anti-cancer drug are in progress. However, all cancer types do not respond to metformin with the same effectiveness or acquire resistance. To understand the mechanism of acquired resistance and possibly its mechanism of action as an anti-proliferative agent, we developed metformin resistant LNCaP prostate cancer cells. Metformin resistant LNCaP cells had an increased proliferation rate, increased migration and invasion ability as compared to the parental cells, and expressed markers of epithelial-mesenchymal transition (EMT). A detailed gene expression microarray comparing the resistant cells to the wild type cells revealed that Edil2, Ereg, Axl, Anax2, CD44 and Anax3 were the top up-regulated genes and calbindin 2 and TPTE (transmembrane phosphatase with tensin homology) and IGF1R were down regulated. We focused on Axl, a receptor tyrosine kinase that has been shown to be up regulated in several drug resistance cancers. Here, we show that the metformin resistant cell line as well as castrate resistant cell lines that over express Axl were more resistant to metformin, as well as to taxotere compared to androgen sensitive LNCaP and CWR22 cells that do not overexpress Axl. Forced overexpression of Axl in LNCaP cells decreased metformin and taxotere sensitivity and knockdown of Axl in resistant cells increased sensitivity to these drugs. Inhibition of Axl activity by R428, a small molecule Axl kinase inhibitor, sensitized metformin resistant cells that overexpressed Axl to metformin. Inhibitors of Axl may enhance tumor responses to metformin and other chemotherapy in cancers that over express Axl.