Qiu Lihua, Zhou Changlin, Sun Yun, Di Wen, Scheffler Erica, Healey Sarah, Kouttab Nicola, Chu Wenming, Wan Yinsheng
Department of OB/GYN, Renji Hospital, Shanghai Jiaotong University, Shanghai 200001, P.R. China.
Int J Oncol. 2006 Oct;29(4):1003-11.
Ovarian cancer remains the leading cause of fatality among all gynecologic cancers, although promising therapies are in the making. It has been speculated that metastasis is critical for ovarian cancer, and yet the molecular mechanisms of metastasis in ovarian cancer are poorly understood. Growth factors have been proven to play important roles in cell migration associated with metastasis, and inhibition of growth factor receptors and their distinct cell signaling pathways has been intensively studied, and yet the uncovered interaction or crosstalk among various growth factor receptors complicates this otherwise promising approach. We investigated the crosstalk between EGFR and TrkB, both of which have been known to be important in cell survival and migration in response to EGF and BDNF. Our results showed that both EGF and BDNF induced cell migration and cell proliferation in cultured human ovarian cancer cells (Caov3 cell line). EGF and BDNF transactivated TrkB and EGFR respectively, and activated downstream cell survival components such as Akt. EGFR and TrkB kinase inhibitors inhibited EGF- and BDNF-induced TrkB and EGFR activation and Akt phosphorylation, and cell proliferation and migration. Using EGFR knockout cells, we further demonstrated that EGFR is required for EGF-induced cell migration. Collectively, our data indicate that EGFR and TrkB crosstalk each other in response to EGF and BDNF, leading to cell survival pathway activation in ovarian cancer cells. Our data suggest that a combination of inhibitors of both receptors with cell survival pathway inhibitors would provide a better outcome in the clinical treatment of ovarian cancer.
卵巢癌仍然是所有妇科癌症中致死的主要原因，尽管有前景的治疗方法正在研发中。据推测，转移对于卵巢癌至关重要，然而卵巢癌转移的分子机制却知之甚少。生长因子已被证明在与转移相关的细胞迁移中起重要作用，对生长因子受体及其独特的细胞信号通路的抑制已得到深入研究，然而各种生长因子受体之间未被发现的相互作用或串扰使这种原本有前景的方法变得复杂。我们研究了表皮生长因子受体（EGFR）和酪氨酸激酶受体B（TrkB）之间的串扰，已知这两者在细胞对表皮生长因子（EGF）和脑源性神经营养因子（BDNF）的存活及迁移反应中都很重要。我们的结果表明，EGF和BDNF均能诱导培养的人卵巢癌细胞（Caov3细胞系）的细胞迁移和细胞增殖。EGF和BDNF分别反式激活TrkB和EGFR，并激活下游细胞存活成分如蛋白激酶B（Akt）。EGFR和TrkB激酶抑制剂可抑制EGF和BDNF诱导的TrkB和EGFR激活以及Akt磷酸化，以及细胞增殖和迁移。使用EGFR基因敲除细胞时，我们进一步证明EGF诱导的细胞迁移需要EGFR。总体而言，我们的数据表明，EGFR和TrkB在对EGF和BDNF的反应中相互串扰，导致卵巢癌细胞中的细胞存活通路激活。我们的数据表明，两种受体的抑制剂与细胞存活通路抑制剂联合使用将在卵巢癌的临床治疗中产生更好的效果。
