Skip to Main content Skip to Navigation
Journal articles

TRAIL induces receptor-interacting protein 1-dependent and caspase-dependent necrosis-like cell death under acidic extracellular conditions.

Abstract : Tumor necrosis factor-alpha-related apoptosis-inducing ligand (TRAIL) is a potential anticancer agent that induces apoptosis in cancer cells but not in most normal cells. How tumor physiology, particularly acidic extracellular pH (pH(e)), would modify sensitivity of cancer cells to TRAIL-induced cell death is not known. We have previously shown that cancer cells, resistant to TRAIL-induced apoptosis at physiologic pH(e) (7.4), could be sensitized to TRAIL at acidic pH(e) (6.5). However, at this acidic pH(e), cell death was necrotic. We show here that, in spite of a necrosis-like cell death morphology, caspases are activated and are necessary for TRAIL-induced cell death at acidic pH(e) in HT29 human colon cancer cells. Furthermore, we observed that, whereas receptor-interacting protein (RIP) was cleaved following TRAIL treatment at physiologic pH(e) (7.4), it was not cleaved following TRAIL treatment at acidic pH(e) (6.5). Moreover, RIP degradation by geldanamycin or decrease expression of RIP by small RNA interference transfection inhibited TRAIL-induced necrosis at acidic pH(e), showing that RIP was necessary for this necrotic cell death pathway. We also show that RIP kinase activity was essential for this cell death pathway. Altogether, we show that, under acidic pH(e) conditions, TRAIL induces a necrosis-like cell death pathway that depends both on caspases and RIP kinase activity. Thus, our data suggest for the first time that RIP-dependent necrosis might be a major death pathway in TRAIL-based therapy in solid tumors with acidic pH(e).
Document type :
Journal articles
Complete list of metadatas

Cited literature [42 references]  Display  Hide  Download

https://hal.archives-ouvertes.fr/hal-00690349
Contributor : Alice Brébion <>
Submitted on : Friday, May 29, 2020 - 11:58:44 PM
Last modification on : Wednesday, October 14, 2020 - 4:03:28 AM

File

2007Meurette-et-alCR_1.pdf
Files produced by the author(s)

Identifiers

Citation

Olivier Meurette, Amélie Rébillard, Laurence Huc, Gwenaëlle Le Moigne, Delphine Merino, et al.. TRAIL induces receptor-interacting protein 1-dependent and caspase-dependent necrosis-like cell death under acidic extracellular conditions.. Cancer Research, American Association for Cancer Research, 2007, 67 (1), pp.218-26. ⟨10.1158/0008-5472.CAN-06-1610⟩. ⟨hal-00690349⟩

Share

Metrics

Record views

563

Files downloads

58