GHRH Antagonist JMR-132 Halts Cancer Cell Growth by Activating p21/waf1

Growth Hormone-Releasing Hormone (GHRH) plays a crucial role in regulating growth hormone secretion, but also directly promotes the proliferation of various cancer cells. Targeting GHRH receptors with antagonists like JMR-132 has shown promise in inhibiting tumor growth. However, the precise molecular mechanisms by which GHRH antagonists exert their anti-proliferative effects, particularly the involvement of key cell cycle regulators like p21/waf1, remained unclear.

Treatment with JMR-132 significantly inhibited the proliferation of cancer cells in a dose- and time-dependent manner, achieving a 55% reduction in cell viability at 10 µM after 48 hours (p<0.001). This anti-proliferative effect was accompanied by a significant increase in the expression of the cell cycle inhibitor p21/waf1, showing a 3.2-fold increase in protein levels compared to untreated controls (p<0.01). > The study definitively showed that silencing p21/waf1 expression with siRNA almost completely abolished the anti-proliferative effects of JMR-132, restoring cell viability by 43% compared to cells treated with JMR-132 alone (p<0.005). Furthermore, JMR-132 treatment led to a 28% increase in cells arrested in the G0/G1 phase of the cell cycle (p<0.01) and a 15% increase in apoptotic cells (p<0.05), effects that were significantly attenuated when p21/waf1 was knocked down. These findings indicate that JMR-132 mediates its growth-inhibitory actions primarily through the upregulation of p21/waf1, leading to cell cycle arrest and apoptosis.