GHRH, besides its neuroendocrine action in controlling the release of GH from the pituitary, stimulates the growth of various cancers in vivo and in vitro by direct mechanism(s). However, the molecular mechanism that mediates these proliferative effects of GHRH in extrapituitary tissues remains poorly characterized. In the present study, we investigated whether the tumor suppressor p21/waf1 is involved in the mediation of the proliferative effects of GHRH in A549 human lung cancer epithelial cells. Exposure of A549 cells to the GHRH antagonist JMR-132 caused a significant inhibition in the rate of cell proliferation. In A549 cells, GHRH suppressed while JMR-132 increased the levels of p21 expression in a dose-dependent manner. This suggests that GHRH could regulate p21 levels. We then evaluated whether p21 is required in A549 cells for the regulation of cell proliferation by GHRH. To this end, we knocked-down p21 expression in A549 cells by siRNA and assessed the effects of antagonist JMR-132 on cell proliferation. We found that the loss of p21 expression abolished the anti-proliferative effects of JMR-132. Suppression of p21 expression by siRNA in human HT29 colon cancer cells and non-transformed mouse osteoblasts KS483 also blocked the anti-proliferative effects of JMR-132 suggesting that the regulation of cell proliferation by GHRH is p21 dependent. These results shed light on the molecular mechanism of action of GHRH antagonists in tumor tissues and suggest that the antineoplastic activity of GHRH antagonists could be considered for the treatment of cancers expressing p21.

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Cancer cells are committed to an actively secretory state that facilitates communication with their microenvironment. We have addressed the role of ERp29, a novel endoplasmic reticulum secretion factor in mammary carcinogenesis using MCF-7 human breast cancer cells as a model. Xenografts originating from cells stably transfected with dominant-negative form of ERp29 were smaller and better differentiated than those derived from cells overexpressing wild-type ERp29. Similar effects were observed by siRNA-mediated ERp29 silencing in xenografts. However, unlike xenografts, the modulation of ERp29 in vitro did not affect the rate of cell proliferation. In addition, we have evaluated the expression of ERp29 in the resting and lactating mammary glands of mice as well as in the human primary breast tumors. About 25% of breast cancers and also lactating mammary glands were expressing ERp29 while the resting glands did not. Taken together these data suggest the active involvement of ERp29 in the malignant conversion of mammary epithelial cells.

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