GHRH Antagonist MZ-5-156 Activates AMPK and Inhibits mTOR in A549 Lung Cancer Cells

Growth hormone-releasing hormone (GHRH), beyond its role in pituitary function, is known to stimulate the growth of various cancers both in vivo and in vitro. Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths, and novel therapeutic strategies are urgently needed. AMP-activated protein kinase (AMPK) is a crucial regulator of cellular proliferation, growth, and metabolism, and its activation is considered a promising strategy for cancer treatment. This study investigates the molecular mechanisms by which GHRH antagonists, specifically MZ-5-156, influence these critical pathways in lung cancer cells, addressing a gap in understanding GHRH's extrapituitary effects.

Researchers utilized human A549 non-small cell lung cancer cells, which endogenously express GHRH receptors, to evaluate the effects of a GHRH antagonist. Cells were treated with GHRH antagonist MZ-5-156 or GHRH(1-29)NH2 to assess their impact on intracellular signaling. As a negative control, HeLa human endometrial cancer cells, which lack GHRH receptors, were also included. The study focused on evaluating the phosphorylation status of AMPK and other related regulatory proteins, including glycogen synthase kinase (GSK)3β, Akt, mammalian target of rapamycin (mTOR), and its downstream target eIF4E, to understand their roles in cell proliferation and protein synthesis.

Treatment of A549 cells with GHRH antagonist MZ-5-156 significantly decreased cell proliferation. This antiproliferative effect was accompanied by a clear activation of AMPK and GSK3β. Furthermore, MZ-5-156 demonstrated a potent inhibitory effect on key pro-growth pathways, specifically inhibiting Akt, mTOR, and its downstream target eIF4E, which are critical regulators of protein synthesis and cell growth. The abstract does not provide specific numerical data (e.g., percentages, fold-changes, or p-values) for these observations. Importantly, the effects of MZ-5-156 were counteracted by the presence of GHRH(1-29)NH2, suggesting a receptor-mediated mechanism.

HeLa human endometrial cancer cells, which do not express GHRH receptors, showed no AMPK activation when treated with GHRH, reinforcing the specificity of the observed effects in GHRH receptor-positive cells. These findings collectively demonstrate a novel role for GHRH antagonists in regulating the AMPK metabolic pathway.