ABSTRACT
The cyclopentenone prostaglandin A1 (PGA1) is an inducer of cell death in cancer cells. However, the mechanism that initiates this cytotoxic response remains elusive. Here we report that PGA1 triggers apoptosis by a process that entails the specific activation of H- and N-Ras isoforms, leading to caspase activation. Cells without H- and N-Ras did not undergo apoptosis upon PGA1 treatment; in these cells, the cellular demise was rescued by overexpression of either H-Ras or N-Ras. Consistently, the mutant H-Ras-C118S, defective for binding PGA1, did not produce cell death. Molecular analysis revealed a key role for the RAF-MEK-ERK signaling pathway in the apoptotic process through the induction of calpain activity and caspase-12 cleavage. We propose that PGA1 evokes a specific physiological cell death program, through H- and N-Ras, but not K-Ras, activation at endomembranes. Our results highlight a novel mechanism that may be of potential interest for tumor treatment.
Subject(s)
Apoptosis/drug effects , Intracellular Membranes/metabolism , Prostaglandins A/pharmacology , ras Proteins/metabolism , Animals , Calpain/metabolism , Cell Line, Tumor , Cysteine/metabolism , Embryo, Mammalian/cytology , Enzyme Activation/drug effects , Extracellular Signal-Regulated MAP Kinases/metabolism , Fibroblasts/cytology , Fibroblasts/drug effects , Fibroblasts/metabolism , Intracellular Membranes/drug effects , Mice , Neoplasms/metabolism , Neoplasms/pathologyABSTRACT
OBJECTIVES: To identify risk factors of asymptomatic vertebral fracture (aVF) in postmenopausal women with osteopenia at the femoral neck and to evaluate the association between the number of aVFs and the risk of major and hip osteoporotic fracture calculated with the FRAX(®) algorithm. STUDY DESIGN: Epidemiological case-series study with data collected transversally. RESULTS: 728 postmenopausal women with osteopenia were included: 284 (39.0%) had aVF, of whom 200 (70.4%) had prior fragility fractures (FF). The likelihood of having an osteoporotic fracture in the next 10 years increased significantly with the number of aVF. The percentage of women with height loss, which was assessed as the difference between the greatest height reported by participants and that measured at inclusion, was higher in women with an aVF (OR 3.77, 95% CI 2.75-5.16, p<0.05). Multivariate analysis showed that prior FF, height loss and race were factors associated with the presence of aVF. CONCLUSIONS: In this group of postmenopausal women with osteopenia at the femoral neck, the presence of an aVF correlated with a higher risk of estimated major osteoporotic and hip fractures as calculated using the FRAX(®) algorithm. Height loss and prior FF were associated with the presence of aVF.
