Publication: PGA(1)-induced apoptosis involves specific activation of H-Ras and N-Ras in cellular endomembranes
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2016
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Anta-Felez, Berta ISCIII 
Perez-Rodriguez, Andrea ISCIII 
Castro, Judith ISCIII
Garcia-Dominguez, Carlota A ISCIII
Ibiza, S CNIC
Martinez, Natalia ISCIII
Dura, Lara M ISCIII
Hernandez, Silvia ISCIII
Gragera, Teresa ISCIII
Peña-Jimenez, Daniel CNIO
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Nature Publishing Group
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Abstract
The cyclopentenone prostaglandin A(1) (PGA(1)) is an inducer of cell death in cancer cells. However, the mechanism that initiates this cytotoxic response remains elusive. Here we report that PGA(1) 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 PGA(1) treatment; in these cells, the cellular demise was rescued by overexpression of either H-Ras or N-Ras. Consistently, the mutant H-Ras-C118-S, defective for binding PGA(1), 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 PGA(1) 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.
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Cell Death Dis. 2016; 7(7):e2311