Chattopadhyay Chandrani, El-Naggar Adel K, Williams Michelle D, Clayman Gary L
Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.
Head Neck. 2008 Aug;30(8):991-1000. doi: 10.1002/hed.20816.
c-Met is upregulated in papillary thyroid carcinoma (PTC) and can be an attractive therapeutic target. We tested the effects of the small molecule c-met inhibitor PHA665752 in blocking c-met-dependent phenotypic effects in PTC cell lines.
PTC patient tissues and cell lines were evaluated for c-met expression. The effect of PHA665752 on c-met phosphorylation, downstream signaling, hepatocyte growth factor (HGF)-dependent cell growth, and induction of apoptosis was studied. The IC(50) of PHA665752 in c-met-expressing PTC cells was determined, and growth curves at 0.1x, 1x, and 10x IC(50) concentrations were obtained. Poly(ADP-ribose) polymerase (PARP) and caspase-9-processing post-PHA665752 treatment were studied as markers of apoptosis, and assays analyzing HGF-dependent cell invasion and migration in the presence and absence of PHA665752 were done.
c-Met was upregulated in most of the patient tissues with PTC and in many PTC cell lines. PHA665752 specifically inhibited c-met phosphorylation, c-met-dependent cell growth, signal transduction, cell survival, cell invasion, and migration in PTC cells with high c-met.
PHA665752 is an effective and specific inhibitor of c-met in PTC cells with high levels of c-met expression.
c-Met在甲状腺乳头状癌（PTC）中表达上调，可能是一个有吸引力的治疗靶点。我们测试了小分子c-met抑制剂PHA665752对PTC细胞系中c-met依赖性表型效应的阻断作用。
评估PTC患者组织和细胞系中的c-met表达。研究了PHA665752对c-met磷酸化、下游信号传导、肝细胞生长因子（HGF）依赖性细胞生长和凋亡诱导的影响。测定了PHA665752在表达c-met的PTC细胞中的半数抑制浓度（IC50），并获得了0.1倍、1倍和10倍IC50浓度下的生长曲线。研究了PHA665752处理后聚（ADP-核糖）聚合酶（PARP）和半胱天冬酶-9的加工情况，作为凋亡的标志物，并进行了分析在有或无PHA665752存在时HGF依赖性细胞侵袭和迁移的试验。
c-Met在大多数PTC患者组织和许多PTC细胞系中表达上调。PHA665752特异性抑制高表达c-met的PTC细胞中的c-met磷酸化、c-met依赖性细胞生长、信号转导、细胞存活、细胞侵袭和迁移。
PHA665752是高表达c-met的PTC细胞中一种有效且特异性的c-met抑制剂。
