Influence of novel KGFR tyrosine kinase inhibitors on KGF-mediated proliferation of breast cancer.
Influence of novel KGFR tyrosine kinase inhibitors on KGF-mediated proliferation of breast cancer.
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发表时间：
2010-12
影响因子：
2
通讯作者：
Meghna Mehta;J. Kesinger;X. Zang;M. Lerner;D. Brackett;R. Brueggemeier;Pui-Kui Li;J. Pento
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作者：
Meghna Mehta;J. Kesinger;X. Zang;M. Lerner;D. Brackett;R. Brueggemeier;Pui-Kui Li;J. Pento
角化细胞生长因子（Keratinocyte growth factor， KGF）作用于KGF受体（KGFR），通过Erk信号通路介导快速刺激乳腺癌细胞增殖和运动。KGF/KGFR信号转导的增强可能是乳腺癌转移进展的早期步骤。KGFR受体模型被用来鉴定选择性KGFR酪氨酸激酶（TK）抑制剂分子，这些分子有可能选择性地与KGFR结合。本研究评估了57种KGFR TK抑制剂化合物对乳腺癌细胞的生物活性。材料和方法在MCF-7乳腺癌细胞中测试了这些化合物抑制kgf介导的乳腺癌细胞增殖的能力。此外，研究了最有效的增殖抑制剂对Erk信号传导和细胞膜KGFR相对密度的影响。结果：57种化合物中有27种对kgf介导的增殖产生20%或更高的抑制作用；而5种化合物的抑制作用大于50%。此外，最有效的抑制剂还能降低Erk信号传导和KGFR的细胞膜密度。结论所检测的化合物似乎是选择性KGFR抑制剂，可抑制kgf介导的活性，降低KGFR在癌细胞上的表达。这些结果可能导致一类新的抗癌药物的发展，以防止转移性癌症的进展。
BACKGROUND Keratinocyte growth factor (KGF) acts at the KGF receptor (KGFR) to produce a rapid stimulation of breast cancer cell proliferation and motility which is mediated via the Erk signaling pathway. Enhancement of KGF/KGFR signal transduction may be an early step in the metastatic progression of breast cancer. Receptor modeling of KGFR was used to identify selective KGFR tyrosine kinase (TK) inhibitor molecules that have the potential to bind selectively to the KGFR. The present study evaluated the biological activity of 57 of these KGFR TK inhibitor compounds on breast cancer cells. MATERIALS AND METHODS These compounds were tested for their ability to inhibit KGF-mediated breast cancer cell proliferation in MCF-7 breast cancer cells. Furthermore, the effects of the most effective proliferation inhibitors were examined on Erk signaling and on the relative density of cell membrane KGFR. RESULTS It was observed that 27 of the 57 compounds tested produced a 20% or greater reduction in KGF-mediated proliferation; while five compounds produced greater than 50% inhibition. In addition, the most potent inhibitors also reduced Erk signaling and cell membrane density of the KGFR. CONCLUSION The compounds examined appear to be selective KGFR inhibitors which inhibit KGF-mediated activity and reduce the expression of KGFR on cancer cells. These results may lead to the development of a novel class of anticancer agents for the prevention of metastatic cancer progression.