Loss of ceramide production confers resistance to radiation-induced apoptosis
- PMID: 9102212
Loss of ceramide production confers resistance to radiation-induced apoptosis
Abstract
Ionizing radiation mediates cell death, in part, through chromosomal damage following one or more cell divisions. X-rays also induce programmed cell death (apoptosis) in some cell types both in vitro and in vivo. Both neutral and acidic sphingomyelinases, which generate the lipid second messenger ceramide, are reported to induce apoptosis following ionizing radiation and other death signals such as tumor necrosis factor alpha and Fas ligand. Herein we report that a loss of ceramide production from a neutral sphingomyelinase generates a radioresistant phenotype as measured by a marked decrease in apoptosis. A WEHI-231 subline made deficient in ceramide production was found to be resistant to apoptosis compared with the parental subline following treatment with X-rays. The resistant subline underwent two to three subsequent cell divisions following X-irradiation, confirming that X-rays induce cell death through both mitotic and apoptotic mechanisms. These data suggest that loss of ceramide production following X-rays represents an extranuclear mechanism for the development of radioresistance. Modulation of extranuclear signals may increase tumor cell killing following radiation and represent new cellular _targets for cancer therapy.
Similar articles
-
Induction of apoptotic cell death and prevention of tumor growth by ceramide analogues in metastatic human colon cancer.Cancer Res. 2001 Feb 1;61(3):1233-40. Cancer Res. 2001. PMID: 11221856
-
Ceramide-induced killing of normal and malignant human lymphocytes is by a non-apoptotic mechanism.Oncogene. 1999 Apr 15;18(15):2499-506. doi: 10.1038/sj.onc.1202622. Oncogene. 1999. PMID: 10229201
-
Resistance to radiation-induced apoptosis in Burkitt's lymphoma cells is associated with defective ceramide signaling.Cancer Res. 1997 Aug 15;57(16):3600-5. Cancer Res. 1997. PMID: 9270034
-
Radiation and ceramide-induced apoptosis.Oncogene. 2003 Sep 1;22(37):5897-906. doi: 10.1038/sj.onc.1206702. Oncogene. 2003. PMID: 12947396 Review.
-
Radiation-induced apoptosis: relevance to radiotherapy.Int J Radiat Oncol Biol Phys. 1995 Nov 1;33(4):781-96. doi: 10.1016/0360-3016(95)00214-8. Int J Radiat Oncol Biol Phys. 1995. PMID: 7591884 Review.
Cited by
-
Interdiction of sphingolipid metabolism to improve standard cancer therapies.Adv Cancer Res. 2013;117:1-36. doi: 10.1016/B978-0-12-394274-6.00001-7. Adv Cancer Res. 2013. PMID: 23290775 Free PMC article. Review.
-
Altered death receptor signaling promotes epithelial-to-mesenchymal transition and acquired chemoresistance.Sci Rep. 2012;2:539. doi: 10.1038/srep00539. Epub 2012 Jul 27. Sci Rep. 2012. PMID: 22844580 Free PMC article.
-
The BCL-2 protein BAK is required for long-chain ceramide generation during apoptosis.J Biol Chem. 2010 Apr 16;285(16):11818-26. doi: 10.1074/jbc.M109.078121. Epub 2010 Feb 18. J Biol Chem. 2010. PMID: 20172858 Free PMC article.
-
The antimicrotubule drug estramustine but not irradiation induces apoptosis in malignant glioma involving AKT and caspase pathways.J Neurooncol. 2002 Jan;56(2):143-8. doi: 10.1023/a:1014562503097. J Neurooncol. 2002. PMID: 11995815
-
Suppression of glucosylceramide synthase restores p53-dependent apoptosis in mutant p53 cancer cells.Cancer Res. 2011 Mar 15;71(6):2276-85. doi: 10.1158/0008-5472.CAN-10-3107. Epub 2011 Jan 28. Cancer Res. 2011. PMID: 21278235 Free PMC article.
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Other Literature Sources
Research Materials
Miscellaneous