Autocrine/paracrine regulation of breast cancer cell proliferation by growth hormone releasing hormone via Ras, Raf, and mitogen-activated protein kinase.
Autocrine/paracrine regulation of breast cancer cell proliferation by growth hormone releasing hormone via Ras, Raf, and mitogen-activated protein kinase.
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DOI：
10.1210/me.2005-0001
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发表时间：
2006-09
影响因子：
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通讯作者：
G. Siriwardana;A. Bradford;D. Coy;P. Zeitler
中科院分区：
文献类型：
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作者：
G. Siriwardana;A. Bradford;D. Coy;P. Zeitler
尽管 GHRH 先前已被证明可以调节乳腺癌细胞的增殖并防止细胞凋亡，但介导这种作用的细胞内途径尚未阐明。外源 GHRH 在 24 小时内刺激 MDA-231 以及转染 GHRH 受体的 T47D 细胞和 MCF-7 细胞中的剂量依赖性增殖反应。 MDA-MB-231 (MDA-231) 细胞的增殖与氚化胸苷摄取的增加相关。此外，GHRH 会迅速刺激 MAPK 的磷酸化。通过用显性失活 Ras 或 Raf 转染细胞或用 Raf 激酶 1 抑制剂预处理细胞，可防止 GHRH 对 MAPK 的磷酸化。 PD98059 对 Ras 和 Raf 的抑制以及对 MAPK 磷酸化的抑制也可阻止 GHRH 诱导的细胞增殖。最后，用生长抑素类似物 BIM23014 预处理细胞也可以阻止 GHRH 诱导的 MAPK 磷酸化和细胞增殖。这些结果表明，GHRH 通过需要 Ras、Raf 和 MAPK 磷酸化的途径刺激 MDA-231 乳腺癌细胞的剂量依赖性细胞增殖。该结果还为 GHRH 和生长抑素在 MDA-231 细胞群维持调节中可能存在的自分泌/旁分泌拮抗作用提供了支持。总而言之，这些研究进一步深入了解 GHRH 作为生长因子在乳腺癌中的可能作用。
Although GHRH has previously been shown to regulate proliferation of breast cancer cells and prevent apoptosis, the intracellular pathways mediating this effect have not been clarified. Exogenous GHRH stimulated a dose-dependent proliferative response within 24 h in MDA-231, as well as in T47D cells and in MCF-7 cells transfected with the GHRH receptor. The proliferation of MDA-MB-231 (MDA-231) cells was associated with an increase in tritiated thymidine uptake. In addition, phosphorylation of MAPK was rapidly stimulated by GHRH. The phosphorylation of MAPK by GHRH was prevented by transfection of the cells with dominant-negative Ras or Raf or by pretreatment of cells with Raf kinase 1 inhibitor. The inhibition of Ras and Raf, as well as the inhibition of MAPK phosphorylation by PD98059, also prevented GHRH-induced cell proliferation. Finally, pretreatment of cells with the somatostatin analog, BIM23014, also prevented GHRH-induced MAPK phosphorylation and cell proliferation. These results indicate that GHRH stimulates dose-dependent cell proliferation of MDA-231 breast cancer cells through a pathway that requires Ras, Raf, and MAPK phosphorylation. The results also provide support for a possible autocrine/paracrine antagonism between GHRH and somatostatin in the regulation of MDA-231 cell population maintenance. Taken together, the studies provide further insight into the possible role of GHRH as a growth factor in breast cancer.