Ras inhibition enhances autophagy, which partially protects cells from death.
Autophagy, a process of regulated turnover of cellular constituents, is essential for normal growth control but may be defective under pathological conditions. The Ras/PI3K/mTOR signaling pathway negatively regulates autophagy. Ras signaling has been documented in a large number of human cancers. In this in-vitro study we examined the effect of the Ras inhibitor Salirasib (S-trans, trans-farnesylthiosalicylic acid; FTS) on autophagy induction and cell viability. We show that Ras inhibition by FTS induced autophagy in several cell lines, including mouse embryonic fibroblasts and the human cancer cell lines HeLa, HCT-116 and DLD-1. The autophagy induced by FTS seems to inhibit the cell death induced by FTS, since in the absence of autophagy the death of FTS-treated cells was enhanced. Therefore, inhibition of autophagy may promote the inhibition of tumor cell growth and the cell death mediated by FTS.
Department of Neurobiology, Tel-Aviv University, Ramat-Aviv, Israel.
Eran
E
Schmukler
Efrat
E
Grinboim
Sari
S
Schokoroy
Adva
A
Amir
Eya
E
Wolfson
Yoel
Y
Kloog
Ronit
R
Pinkas-Kramarski
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects*; D000071187:Autophagy-Related Protein 5; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian / Q000166:cytology; D005204:Farnesol / Q000031:analogs & derivatives* / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D012459:Salicylates / Q000494:pharmacology*; D018631:ras Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000970:Antineoplastic Agents; C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D008869:Microtubule-Associated Proteins; D012459:Salicylates; C093323:farnesylthiosalicylic acid; D049452:Green Fluorescent Proteins; D005204:Farnesol; D018631:ras Proteins