Protein kinase C zeta regulates human pancreatic cancer cell transformed growth and invasion through a STAT3-dependent mechanism.
Protein kinase C zeta regulates human pancreatic cancer cell transformed growth and invasion through a STAT3-dependent mechanism.
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蛋白激酶C Zeta调节人胰腺癌细胞通过STAT3依赖机制转化生长和侵袭。
DOI：
10.1371/journal.pone.0072061
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Murray NR
中科院分区：
文献类型：
--
作者：
Butler AM;Scotti Buzhardt ML;Li S;Smith KE;Fields AP;Murray NR
胰腺癌是一种侵袭性很强的疾病，几乎没有治疗选择。在本研究中，我们探讨了蛋白激酶C Zeta(PKCζ)在胰腺癌细胞中的作用。已有研究表明，PKCζ可以作为肿瘤抑制因子，也可以作为肿瘤促进剂，取决于细胞环境。我们发现PKCζ在人原发胰腺肿瘤中表达维持或升高，但从未丢失，这与PKCζ在胰腺癌表型中起促进作用一致。基因抑制蛋白激酶Cζ降低了体外培养的人胰腺癌细胞的贴壁生长、细胞存活和贴壁非贴壁生长。此外，抑制PKCζ通过抑制肿瘤细胞增殖和增加肿瘤坏死来缩小体内原位肿瘤的大小。此外，抑制PKCζ在体内减少肿瘤转移，并在体外导致胰腺癌细胞侵袭的相应减少。信号转导和转录激活因子3(STAT3)在胰腺癌中具有结构性活性，对胰腺癌细胞的存活和转移起重要作用。有趣的是，在体外和体内，抑制蛋白激酶Cζ显著降低了胰腺癌细胞中STAT3的结构性激活。STAT3的药理抑制模拟了PKCζ抑制的表型，在PKCζ缺陷的细胞中，表达具有结构性活性的STAT3结构挽救了转化的表型。结论：PKCζ是胰腺癌细胞转化生长、侵袭和体内成瘤所必需的，并且是PKCζ促胰腺癌细胞致癌作用的重要下游介导物。
Pancreatic cancer is a very aggressive disease with few therapeutic options. In this study, we investigate the role of protein kinase C zeta (PKCζ) in pancreatic cancer cells. PKCζ has been shown to act as either a tumor suppressor or tumor promoter depending upon the cellular context. We find that PKCζ expression is either maintained or elevated in primary human pancreatic tumors, but is never lost, consistent with PKCζ playing a promotive role in the pancreatic cancer phenotype. Genetic inhibition of PKCζ reduced adherent growth, cell survival and anchorage-independent growth of human pancreatic cancer cells in vitro. Furthermore, PKCζ inhibition reduced orthotopic tumor size in vivo by inhibiting tumor cell proliferation and increasing tumor necrosis. In addition, PKCζ inhibition reduced tumor metastases in vivo, and caused a corresponding reduction in pancreatic cancer cell invasion in vitro. Signal transducer and activator of transcription 3 (STAT3) is often constitutively active in pancreatic cancer, and plays an important role in pancreatic cancer cell survival and metastasis. Interestingly, inhibition of PKCζ significantly reduced constitutive STAT3 activation in pancreatic cancer cells in vitro and in vivo. Pharmacologic inhibition of STAT3 mimicked the phenotype of PKCζ inhibition, and expression of a constitutively active STAT3 construct rescued the transformed phenotype in PKCζ-deficient cells. We conclude that PKCζ is required for pancreatic cancer cell transformed growth and invasion in vitro and tumorigenesis in vivo, and that STAT3 is an important downstream mediator of the pro-carcinogenic effects of PKCζ in pancreatic cancer cells.
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影响因子：
4.9
作者：
Calcagno, Shelly R.;Li, Shuhua;Shahid, Muhammad W.;Wallace, Michael B.;Leitges, Michael;Fields, Alan P.;Murray, Nicole R.
通讯作者：
Murray, Nicole R.
DOI：
10.1124/jpet.109.162669
发表时间：
2010-05-01
影响因子：
3.5
作者：
Jaganathan, Soumya;Yue, Peibin;Turkson, James
通讯作者：
Turkson, James
影响因子：
11.2
作者：
Lebedeva, IV;Sarkar, D;Fisher, PB
通讯作者：
Fisher, PB
影响因子：
50.3
作者：
Fukuda A;Wang SC;Morris JP 4th;Folias AE;Liou A;Kim GE;Akira S;Boucher KM;Firpo MA;Mulvihill SJ;Hebrok M
通讯作者：
Hebrok M
影响因子：
11.2
作者：
Cohen, Ezra Eddy Wyssant;Lingen, Mark W.;Rosner, Marsha Rich
通讯作者：
Rosner, Marsha Rich