Inhibition of basal and mitogen-stimulated pancreatic cancer cell growth by cyclin D1 antisense is associated with loss of tumorigenicity and potentiation of cytotoxicity to cisplatinum
Inhibition of basal and mitogen-stimulated pancreatic cancer cell growth by cyclin D1 antisense is associated with loss of tumorigenicity and potentiation of cytotoxicity to cisplatinum
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DOI：
10.1172/jci1323
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发表时间：
1998-01-15
影响因子：
15.9
通讯作者：
Korc, M
中科院分区：
文献类型：
--
作者：
Kornmann, M;Arber, N;Korc, M
细胞周期蛋白D1属于蛋白激酶家族，参与细胞周期调控。最近的研究表明，细胞周期蛋白D1水平升高与胰腺癌生存率下降相关。在本研究中，我们在PANC-1人胰腺癌细胞中以稳定的方式表达了cyclin D1反义cDNA构建体，反义构建体的表达引起cyclin D1 mRNA和蛋白水平以及cyclin D1相关激酶活性的降低。反义表达克隆显示倍增时间显著增加，降低锚定依赖性和非依赖性的基础生长，并在裸鼠体内完全丧失致瘤性。EGF、FGF-2和IGF-I在反义表达克隆中增强丝裂原活化蛋白激酶活性，但未能刺激其增殖。相反，所有三种生长因子在亲本细胞中都具有促有丝分裂作用。顺铂对细胞增殖的抑制作用在反义表达克隆中明显增强。这些发现表明，细胞周期蛋白D1的过度表达有助于在人类胰腺癌的异常生长和致瘤性和胰腺癌的耐药性的化疗药物。
Cyclin D1 belongs to a family of protein kinases that have been implicated in cell cycle regulation. Recent studies have demonstrated that elevated cyclin D1 levels correlate with decreased survival in human pancreatic cancer. In this study we expressed in a stable manner a cyclin D1 antisense cDNA construct in PANC-1 human pancreatic cancer cells, Expression of the antisense construct caused a decrease in cyclin D1 mRNA and protein levels and in cyclin D1-associated kinase activity. Antisense expressing clones displayed significantly increased doubling times, decreased anchorage-dependent and -independent basal growth, and complete loss of tumorigenicity in nude mice. EGF, FGF-2, and IGF-I enhanced mitogen-activated protein kinase activity in antisense expressing clones, but failed to stimulate their proliferation. In contrast, all three growth factors were mitogenic in parental cells. Furthermore, the inhibitory effect of cisplatinum on cell proliferation was enhanced markedly in the antisense expressing clones. These findings indicate that cyclin D1 overexpression contributes to abnormal growth and tumorigenicity in human pancreatic cancer and to the resistance of pancreatic cancer to chemotherapeutic agents.