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S1P lyase regulates DNA damage responses through a novel sphingolipid feedback mechanism.
Cell Death Dis 2011; 2:e119CD

Abstract

The injurious consequences of ionizing radiation (IR) to normal human cells and the acquired radioresistance of cancer cells represent limitations to cancer radiotherapy. IR induces DNA damage response pathways that orchestrate cell cycle arrest, DNA repair or apoptosis such that irradiated cells are either repaired or eliminated. Concomitantly and independent of DNA damage, IR activates acid sphingomyelinase (ASMase), which generates ceramide, thereby promoting radiation-induced apoptosis. However, ceramide can also be metabolized to sphingosine-1-phosphate (S1P), which acts paradoxically as a radioprotectant. Thus, sphingolipid metabolism represents a radiosensitivity pivot point, a notion supported by genetic evidence in IR-resistant cancer cells. S1P lyase (SPL) catalyzes the irreversible degradation of S1P in the final step of sphingolipid metabolism. We show that SPL modulates the kinetics of DNA repair, speed of recovery from G2 cell cycle arrest and the extent of apoptosis after IR. SPL acts through a novel feedback mechanism that amplifies stress-induced ceramide accumulation, and downregulation/inhibition of either SPL or ASMase prevents premature cell cycle progression and mitotic death. Further, oral administration of an SPL inhibitor to mice prolonged their survival after exposure to a lethal dose of total body IR. Our findings reveal SPL to be a regulator of ASMase, the G2 checkpoint and DNA repair and a novel target for radioprotection.

Authors+Show Affiliations

Center for Cancer Research, Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland, CA 94609-1673, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, American Recovery and Reinvestment Act
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21368890

Citation

Kumar, A, et al. "S1P Lyase Regulates DNA Damage Responses Through a Novel Sphingolipid Feedback Mechanism." Cell Death & Disease, vol. 2, 2011, pp. e119.
Kumar A, Oskouian B, Fyrst H, et al. S1P lyase regulates DNA damage responses through a novel sphingolipid feedback mechanism. Cell Death Dis. 2011;2:e119.
Kumar, A., Oskouian, B., Fyrst, H., Zhang, M., Paris, F., & Saba, J. D. (2011). S1P lyase regulates DNA damage responses through a novel sphingolipid feedback mechanism. Cell Death & Disease, 2, pp. e119. doi:10.1038/cddis.2011.3.
Kumar A, et al. S1P Lyase Regulates DNA Damage Responses Through a Novel Sphingolipid Feedback Mechanism. Cell Death Dis. 2011 Feb 10;2:e119. PubMed PMID: 21368890.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - S1P lyase regulates DNA damage responses through a novel sphingolipid feedback mechanism. AU - Kumar,A, AU - Oskouian,B, AU - Fyrst,H, AU - Zhang,M, AU - Paris,F, AU - Saba,J D, Y1 - 2011/02/10/ PY - 2011/3/4/entrez PY - 2011/3/4/pubmed PY - 2011/8/6/medline SP - e119 EP - e119 JF - Cell death & disease JO - Cell Death Dis VL - 2 N2 - The injurious consequences of ionizing radiation (IR) to normal human cells and the acquired radioresistance of cancer cells represent limitations to cancer radiotherapy. IR induces DNA damage response pathways that orchestrate cell cycle arrest, DNA repair or apoptosis such that irradiated cells are either repaired or eliminated. Concomitantly and independent of DNA damage, IR activates acid sphingomyelinase (ASMase), which generates ceramide, thereby promoting radiation-induced apoptosis. However, ceramide can also be metabolized to sphingosine-1-phosphate (S1P), which acts paradoxically as a radioprotectant. Thus, sphingolipid metabolism represents a radiosensitivity pivot point, a notion supported by genetic evidence in IR-resistant cancer cells. S1P lyase (SPL) catalyzes the irreversible degradation of S1P in the final step of sphingolipid metabolism. We show that SPL modulates the kinetics of DNA repair, speed of recovery from G2 cell cycle arrest and the extent of apoptosis after IR. SPL acts through a novel feedback mechanism that amplifies stress-induced ceramide accumulation, and downregulation/inhibition of either SPL or ASMase prevents premature cell cycle progression and mitotic death. Further, oral administration of an SPL inhibitor to mice prolonged their survival after exposure to a lethal dose of total body IR. Our findings reveal SPL to be a regulator of ASMase, the G2 checkpoint and DNA repair and a novel target for radioprotection. SN - 2041-4889 UR - https://www.unboundmedicine.com/medline/citation/21368890/S1P_lyase_regulates_DNA_damage_responses_through_a_novel_sphingolipid_feedback_mechanism_ L2 - http://dx.doi.org/10.1038/cddis.2011.3 DB - PRIME DP - Unbound Medicine ER -