Protein kinase C mediates epidermal growth factor-induced growth of head and neck tumor cells by regulating mitogen-activated protein kinase
Protein kinase C mediates epidermal growth factor-induced growth of head and neck tumor cells by regulating mitogen-activated protein kinase
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DOI：
10.1158/0008-5472.can-05-3139
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发表时间：
2006-06-15
期刊：
影响因子：
11.2
通讯作者：
Rosner, Marsha Rich
中科院分区：
文献类型：
--
作者：
Cohen, Ezra Eddy Wyssant;Lingen, Mark W.;Rosner, Marsha Rich
蛋白激酶C（PKC）zeta已被认为是某些细胞类型中表皮生长因子（EGF）受体（EGFR）信号传导的介体。由于EGFR在头颈部鳞状细胞癌（SCCHN）中广泛表达，并在肿瘤进展中起关键作用，因此我们确定了PKC zeta是否是肿瘤细胞增殖和存活所必需的。在正常口腔粘膜、异型增生、癌以及SCCHN肿瘤细胞系中检查总的和磷酸化的PKC zeta表达，发现从正常到恶性组织中活化的PKC zeta表达显著增加。PKC zeta活性是EGF诱导的细胞外信号调节激酶（ERK）激活所必需的正常人成人表皮角质形成细胞和五个SCCHN细胞系。SCCHN细胞表达组成性激活的EGFR家族受体，抑制EGFR或丝裂原活化蛋白激酶（MAPK）活性可抑制DNA合成。与此观察结果一致，使用激酶死亡的PKC zeta突变体或肽抑制剂抑制PKC zeta抑制自分泌和EGF诱导的DNA合成。最后，PKC zeta抑制增强了MAPK/ERK激酶（U 0126）和广谱PKC zeta抑制剂（氯化白屈菜红碱）的作用，并降低了SCCHN细胞系中的细胞增殖。结果表明：（a）PKC zeta与SCCHN进展相关，（B）PKC zeta介导角质形成细胞和SCCHN细胞系中EGF刺激的MAPK活化，（c）PKC zeta介导SCCHN细胞系中EGFR和MAPK依赖性增殖;（d）PKC zeta抑制剂与靶向相似或互补信号传导途径的其他抑制剂相加作用。
Protein kinase C (PKC) zeta has been implicated as a mediator of epidermal growth factor (EGF) receptor (EGFR) signaling in certain cell types. Because EGFR is ubiquitously expressed in squamous cell carcinomas of the head and neck (SCCHN) and plays a key role in tumor progression, we determined whether PKC zeta is required for tumor cell proliferation and viability. Examination of total and phosphorylated PKC zeta expression in normal oral mucosa, dysplasia, and carcinoma as well as SCCHN tumor cell lines revealed a significant increase in activated PKC zeta expression from normal to malignant tissue. PKC zeta activity is required for EGF-induced extracellular signal-regulated kinase (ERK) activation in both normal human adult epidermal keratinocytes and five of seven SCCHN cell lines. SCCHN cells express constitutively activated EGFR family receptors, and inhibition of either EGFR or mitogen-activated protein kinase (MAPK) activity suppressed DNA synthesis. Consistent with this observation, inhibition of PKC zeta using either kinase-dead PKC zeta mutant or peptide inhibitor suppressed autocrine and EGF-induced DNA synthesis. Finally, PKC zeta inhibition enhanced the effects of both MAPK/ERK kinase (U0126) and broad spectrum PKC zeta inhibitor (chelerythrine chloride) and decreased cell proliferation in SCCHN cell lines. The results indicate that (a) PKC zeta is associated with SCCHN progression, (b) PKC zeta mediates EGF-stimulated MAPK activation in keratinocytes and SCCHN cell lines, (c) PKC zeta mediates EGFR and MAPK-dependent proliferation in SCCHN cell lines; and (d) PKC zeta inhibitors function additively with other inhibitors that target similar or complementary signaling pathways.