PGA1-induced apoptosis involves specific activation of H-Ras and N-Ras in cellular endomembranes

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.

Infection of Galleria mellonella (Lepidoptera) Larvae With the Entomopathogenic Fungus Conidiobolus coronatus (Entomophthorales) Induces Apoptosis of Hemocytes and Affects the Concentration of Eicosanoids in the Hemolymph

“…Cyclopentenone prostaglandins such as PGA1 and PGA2 have been found to inactivate p53-dependent transcription and induce p53-independent apoptotic cell death ( Lee et al, 2020 ). More specifically, PGA1 appears to induce apoptosis in mammalian cells by specifically binding to H- and N-Ras on endomembranes and activating them ( Anta et al, 2016 ).…”

Oxylipin biosynthesis reinforces cellular senescence and allows detection of senolysis

“…Prostaglandins reinforce senescence via positive ras/ p53 feedback H-RAS is activated by exogenous 15d-PGJ2 at 3-5 mM (Oliva et al, 2003), roughly the dihomo-15d-PGJ2 level at which senescent cells and other cyclopentenone prostaglandins activate other RAS isoforms or similar GTPases (Anta et al, 2016;Renedo et al, 2007;Wall et al, 2015). We hypothesized that constitutive RAS activation might drive senescence in response to the elevated dihomo-15d-PGJ2.…”

Placental Ras Regulates Inflammation Associated with Maternal Obesity

“…This finding corroborates other studies in nongestational tissues which have found overexpression of Ras under other inflammatory conditions such as in cancers [ 48 – 50 ], cigarette smoking [ 51 ], diabetes, and obesity [ 52 , 53 ]. In addition to inflammation, apoptotic signals can also activate Ras [ 54 ]. Although beyond the scope of the current study, the effects on placental Ras expression following exposure to apoptosis markers such as caspases or PARP (a marker of repair and cell death) warrants further study.…”