Lee Mi-Sook, Kim Hwang-Phill, Kim Tae-You, Lee Jung Weon
Department of Pharmacy, Research Institute of Pharmaceutical Sciences, Cell Dynamics Research Center, College of Pharmacy, Seoul National University, 599, Gwanak-ro, Gwanak-gu, Seoul 151-742, Republic of Korea.
Biochim Biophys Acta. 2012 Feb;1823(2):514-23. doi: 10.1016/j.bbamcr.2011.11.017. Epub 2011 Dec 9.
Although cancers can be initially treated with the epidermal growth factor receptor (EGFR) inhibitor, gefitinib, continued gefitinib therapy does not benefit the survival of patients due to acquired resistance through EGFR mutations, c-MET amplification, or epithelial-mesenchymal transition (EMT). It is of further interest to determine whether mesenchymal-like, but not epithelial-like, cancer cells can become resistant to gefitinib by bypassing EGFR signaling and acquiring alternative routes of proliferative and survival signaling. Here we examined whether gefitinib resistance of cancer cells can be caused by transmembrane 4 L six family member 5 (TM4SF5), which has been shown to induce EMT via cytosolic p27Kip1 stabilization. Gefitinib-resistant cells exhibited higher and/or sustained TM4SF5 expression, cytosolic p27Kip1 stabilization, and mesenchymal phenotypes, compared with gefitinib-sensitive cells. Conversion of gefitinib-sensitive to -resistant cells by introduction of the T790M EGFR mutation caused enhanced and sustained expression of TM4SF5, phosphorylation of p27Kip1 Ser10 (responsible for cytosolic location), loss of E-cadherin from cell-cell contacts, and gefitinib-resistant EGFR and survival signaling activities. Additionally, TM4SF5 overexpression lessened the sensitivity of NSCLC cells to gefitinib. Suppression of TM4SF5 or p27Kip1 in gefitinib-resistant cells via the T790M EGFR mutation or TM4SF5 expression rendered them gefitinib-sensitive, displaying more epithelial-like and less mesenchymal-like characteristics. Together, these results indicate that TM4SF5-mediated EMT may have an important function in the gefitinib resistance of cancer cells.
尽管癌症最初可以用表皮生长因子受体（EGFR）抑制剂吉非替尼进行治疗，但由于通过EGFR突变、c-MET扩增或上皮-间质转化（EMT）导致获得性耐药，持续使用吉非替尼治疗并不能使患者生存获益。进一步研究确定间充质样而非上皮样癌细胞是否可以通过绕过EGFR信号传导并获得增殖和生存信号的替代途径而对吉非替尼产生耐药性，这一点很有意义。在这里，我们研究了癌细胞对吉非替尼的耐药性是否可能由跨膜4 L六家族成员5（TM4SF5）引起，TM4SF5已被证明可通过胞质p27Kip1稳定诱导EMT。与吉非替尼敏感细胞相比，吉非替尼耐药细胞表现出更高和/或持续的TM4SF5表达、胞质p27Kip1稳定和间充质表型。通过引入T790M EGFR突变将吉非替尼敏感细胞转化为耐药细胞，导致TM4SF5表达增强和持续、p27Kip1 Ser10磷酸化（负责胞质定位）、细胞间接触中E-钙黏蛋白丧失以及吉非替尼耐药的EGFR和生存信号活性。此外，TM4SF5过表达降低了NSCLC细胞对吉非替尼的敏感性。通过T790M EGFR突变或TM4SF5表达抑制吉非替尼耐药细胞中的TM4SF5或p27Kip1，使其对吉非替尼敏感，表现出更多上皮样和更少间充质样特征。总之，这些结果表明TM4SF5介导的EMT可能在癌细胞对吉非替尼的耐药性中起重要作用。
