The protein disulfide isomerases PDIA4 and PDIA6 mediate resistance to cisplatin-induced cell death in lung adenocarcinoma.
(2014) Cell Death & Differentiation — Vol. 21, n° 5, p. 685-695 (2014)
Files
pdfdocument.pdf
Restricted Access - Adobe PDF
- 2.69 MB
Details
- Authors
- Abstract
- Intrinsic and acquired chemoresistance are frequent causes of cancer eradication failure. Thus, long-term cis-diaminedichloroplatine(II) (CDDP) or cisplatin treatment is known to promote tumor cell resistance to apoptosis induction via multiple mechanisms involving gene expression modulation of oncogenes, tumor suppressors and blockade of pro-apoptotic mitochondrial membrane permeabilization. Here, we demonstrate that CDDP-resistant non-small lung cancer cells undergo profound remodeling of their endoplasmic reticulum (ER) proteome (>80 proteins identified by proteomics) and exhibit a dramatic overexpression of two protein disulfide isomerases, PDIA4 and PDIA6, without any alteration in ER-cytosol Ca(2+) fluxes. Using pharmacological and genetic inhibition, we show that inactivation of both proteins directly stimulates CDDP-induced cell death by different cellular signaling pathways. PDIA4 inactivation restores a classical mitochondrial apoptosis pathway, while knockdown of PDIA6 favors a non-canonical cell death pathway sharing some necroptosis features. Overexpression of both proteins has also been found in lung adenocarcinoma patients, suggesting a clinical importance of these proteins in chemoresistance.
- Affiliations
Citations
Tufo, G., Jones, A. W. E., Wang, Z., Hamelin, J., Tajeddine, N., Esposti, D. D., Martel, C., Boursier, C., Gallerne, C., Migdal, C., Lemaire, C., Szabadkai, G., Lemoine, A., Kroemer, G., & Brenner, C. (2014). The protein disulfide isomerases PDIA4 and PDIA6 mediate resistance to cisplatin-induced cell death in lung adenocarcinoma. Cell Death & Differentiation, 21(5), 685-695. https://doi.org/10.1038/cdd.2013.193 (Original work published 2014)