Alper O, Hacker N F, Cho-Chung Y S
Cellular Biochemistry Section, Laboratory of Tumor Immunology and Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland MD 20892-1750, USA.
Oncogene. 1999 Sep 2;18(35):4999-5004. doi: 10.1038/sj.onc.1202830.
Expression of the RIalpha subunit of cAMP-dependent protein kinase type I is increased in human cancers in which an autocrine pathway for epidermal growth factor-related growth factors is activated. We have investigated the effect of sequence-specific inhibition of RIalpha gene expression on ovarian cancer cell growth. We report that RIalpha antisense treatment results in a reduction in RIalpha expression and protein kinase A type I, and inhibition of cell growth. The growth inhibition was accompanied by changes in cell morphology and appearance of apoptotic nuclei. In addition, EGF receptor, c-erbB-2 and c-erbB-3 levels were reduced, and the basal and EGF-stimulated mitogen-activated protein kinase activities were reduced. Protein kinase A type I and EGF receptor levels were also reduced in cells overexpressing EGF receptor antisense cDNA. These results suggest that the antisense depletion of RIalpha leads to blockade of both the serine-threonine kinase and the tyrosine kinase signaling pathways resulting in arrest of ovarian cancer cell growth.
I型环磷酸腺苷依赖性蛋白激酶的RIα亚基在激活表皮生长因子相关生长因子自分泌途径的人类癌症中表达增加。我们研究了RIα基因表达的序列特异性抑制对卵巢癌细胞生长的影响。我们报告，RIα反义治疗导致RIα表达和I型蛋白激酶A减少，并抑制细胞生长。生长抑制伴随着细胞形态的改变和凋亡细胞核的出现。此外，表皮生长因子受体、c-erbB-2和c-erbB-3水平降低，基础和表皮生长因子刺激的丝裂原活化蛋白激酶活性降低。在过表达表皮生长因子受体反义cDNA的细胞中，I型蛋白激酶A和表皮生长因子受体水平也降低。这些结果表明，RIα的反义缺失导致丝氨酸-苏氨酸激酶和酪氨酸激酶信号通路的阻断，从而导致卵巢癌细胞生长停滞。
