Acid ceramidase upregulation in prostate cancer cells confers resistance to radiation: AC inhibition, a potential radiosensitizer

Ayman E.M. Mahdy; Joseph C. Cheng; Jun Li; Saeed Elojeimy; William D. Meacham; Lorianne S. Turner; Aiping Bai; Christopher R. Gault; Alex S. McPherson; Nicole Garcia; Thomas H. Beckham; Antonio Saad; Alicja Bielawska; Jacek Bielawski; Yusuf A. Hannun; Thomas E. Keane; Mohhammed I. Taha; Hisham M. Hammouda; James S. Norris; Xiang Liu

doi:10.1038/mt.2008.281

Acid ceramidase upregulation in prostate cancer cells confers resistance to radiation: AC inhibition, a potential radiosensitizer

Ayman E.M. Mahdy, Joseph C. Cheng, Jun Li, Saeed Elojeimy, William D. Meacham, Lorianne S. Turner, Aiping Bai, Christopher R. Gault, Alex S. McPherson, Nicole Garcia, Thomas H. Beckham, Antonio Saad, Alicja Bielawska, Jacek Bielawski, Yusuf A. Hannun, Thomas E. Keane, Mohhammed I. Taha, Hisham M. Hammouda, James S. Norris, Xiang Liu

Obstetrics & Gynecology

Research output: Contribution to journal › Article › peer-review

105 Scopus citations

Abstract

Radiation resistance in a subset of prostate tumors remains a challenge to prostate cancer radiotherapy. The current study on the effects of radiation on prostate cancer cells reveals that radiation programs an unpredicted resistance mechanism by upregulating acid ceramidase (AC). Irradiated cells demonstrated limited changes of ceramide levels while elevating levels of sphingosine and sphingosine-1-phosphate. By genetically downregulating AC with small interfering RNA (siRNA), we observed radiosensitization of cells using clonogenic and cytotoxicity assays. Conversely, AC overexpression further decreased sensitivity to radiation. We also observed that radiation-induced AC upregulation was sufficient to create cross-resistance to chemotherapy as demonstrated by decreased sensitivity to Taxol and C₆ ceramide compared to controls. Lower levels of caspase 3/7 activity were detected in cells pretreated with radiation, also indicating increased resistance. Finally, utilization of the small molecule AC inhibitor, LCL385, sensitized PPC-1 cells to radiation and significantly decreased tumor xenograft growth. These data suggest a new mechanism of cancer cell resistance to radiation, through upregulation of AC that is, in part, mediated by application of the therapy itself. An improved understanding of radiotherapy and the application of combination therapy achieved in this study offer new opportunities for the modulation of radiation effects in the treatment of cancer.

Original language	English (US)
Pages (from-to)	430-438
Number of pages	9
Journal	Molecular Therapy
Volume	17
Issue number	3
DOIs	https://doi.org/10.1038/mt.2008.281
State	Published - 2009

ASJC Scopus subject areas

Molecular Medicine
Molecular Biology
Genetics
Pharmacology
Drug Discovery

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10.1038/mt.2008.281

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Mahdy, A. E. M., Cheng, J. C., Li, J., Elojeimy, S., Meacham, W. D., Turner, L. S., Bai, A., Gault, C. R., McPherson, A. S., Garcia, N., Beckham, T. H., Saad, A., Bielawska, A., Bielawski, J., Hannun, Y. A., Keane, T. E., Taha, M. I., Hammouda, H. M., Norris, J. S., & Liu, X. (2009). Acid ceramidase upregulation in prostate cancer cells confers resistance to radiation: AC inhibition, a potential radiosensitizer. Molecular Therapy, 17(3), 430-438. https://doi.org/10.1038/mt.2008.281

Mahdy, AEM, Cheng, JC, Li, J, Elojeimy, S, Meacham, WD, Turner, LS, Bai, A, Gault, CR, McPherson, AS, Garcia, N, Beckham, TH, Saad, A, Bielawska, A, Bielawski, J, Hannun, YA, Keane, TE, Taha, MI, Hammouda, HM, Norris, JS & Liu, X 2009, 'Acid ceramidase upregulation in prostate cancer cells confers resistance to radiation: AC inhibition, a potential radiosensitizer', Molecular Therapy, vol. 17, no. 3, pp. 430-438. https://doi.org/10.1038/mt.2008.281

@article{d5a6ad6f81674881b4ee77478056176d,

title = "Acid ceramidase upregulation in prostate cancer cells confers resistance to radiation: AC inhibition, a potential radiosensitizer",

abstract = "Radiation resistance in a subset of prostate tumors remains a challenge to prostate cancer radiotherapy. The current study on the effects of radiation on prostate cancer cells reveals that radiation programs an unpredicted resistance mechanism by upregulating acid ceramidase (AC). Irradiated cells demonstrated limited changes of ceramide levels while elevating levels of sphingosine and sphingosine-1-phosphate. By genetically downregulating AC with small interfering RNA (siRNA), we observed radiosensitization of cells using clonogenic and cytotoxicity assays. Conversely, AC overexpression further decreased sensitivity to radiation. We also observed that radiation-induced AC upregulation was sufficient to create cross-resistance to chemotherapy as demonstrated by decreased sensitivity to Taxol and C6 ceramide compared to controls. Lower levels of caspase 3/7 activity were detected in cells pretreated with radiation, also indicating increased resistance. Finally, utilization of the small molecule AC inhibitor, LCL385, sensitized PPC-1 cells to radiation and significantly decreased tumor xenograft growth. These data suggest a new mechanism of cancer cell resistance to radiation, through upregulation of AC that is, in part, mediated by application of the therapy itself. An improved understanding of radiotherapy and the application of combination therapy achieved in this study offer new opportunities for the modulation of radiation effects in the treatment of cancer.",

author = "Mahdy, {Ayman E.M.} and Cheng, {Joseph C.} and Jun Li and Saeed Elojeimy and Meacham, {William D.} and Turner, {Lorianne S.} and Aiping Bai and Gault, {Christopher R.} and McPherson, {Alex S.} and Nicole Garcia and Beckham, {Thomas H.} and Antonio Saad and Alicja Bielawska and Jacek Bielawski and Hannun, {Yusuf A.} and Keane, {Thomas E.} and Taha, {Mohhammed I.} and Hammouda, {Hisham M.} and Norris, {James S.} and Xiang Liu",

note = "Funding Information: This work was supported by the National Institutes of Health (NIH)/ National Cancer Institute PO1 CA97132; Division of Laboratory Animal Research, NIH, C06 RR015455; and the Medical University of South Carolina (MUSC) Lipidomics Core, NIH, C06 RR018823. The technical assistance of Margaret Kelly of the MUSC Hollings Cancer Center Microscopy Core Facility is greatly appreciated. We are also thankful to Janie Nelson for excellent secretarial assistance, and S. Tucker Marrison, Xiaoyi Zhang, and Ben Gilbertson for their help in preparing this manuscript.",

year = "2009",

doi = "10.1038/mt.2008.281",

language = "English (US)",

volume = "17",

pages = "430--438",

journal = "Molecular Therapy",

issn = "1525-0016",

publisher = "Cell Press",

number = "3",

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TY - JOUR

T1 - Acid ceramidase upregulation in prostate cancer cells confers resistance to radiation

T2 - AC inhibition, a potential radiosensitizer

AU - Mahdy, Ayman E.M.

AU - Cheng, Joseph C.

AU - Li, Jun

AU - Elojeimy, Saeed

AU - Meacham, William D.

AU - Turner, Lorianne S.

AU - Bai, Aiping

AU - Gault, Christopher R.

AU - McPherson, Alex S.

AU - Garcia, Nicole

AU - Beckham, Thomas H.

AU - Saad, Antonio

AU - Bielawska, Alicja

AU - Bielawski, Jacek

AU - Hannun, Yusuf A.

AU - Keane, Thomas E.

AU - Taha, Mohhammed I.

AU - Hammouda, Hisham M.

AU - Norris, James S.

AU - Liu, Xiang

N1 - Funding Information: This work was supported by the National Institutes of Health (NIH)/ National Cancer Institute PO1 CA97132; Division of Laboratory Animal Research, NIH, C06 RR015455; and the Medical University of South Carolina (MUSC) Lipidomics Core, NIH, C06 RR018823. The technical assistance of Margaret Kelly of the MUSC Hollings Cancer Center Microscopy Core Facility is greatly appreciated. We are also thankful to Janie Nelson for excellent secretarial assistance, and S. Tucker Marrison, Xiaoyi Zhang, and Ben Gilbertson for their help in preparing this manuscript.

PY - 2009

Y1 - 2009

N2 - Radiation resistance in a subset of prostate tumors remains a challenge to prostate cancer radiotherapy. The current study on the effects of radiation on prostate cancer cells reveals that radiation programs an unpredicted resistance mechanism by upregulating acid ceramidase (AC). Irradiated cells demonstrated limited changes of ceramide levels while elevating levels of sphingosine and sphingosine-1-phosphate. By genetically downregulating AC with small interfering RNA (siRNA), we observed radiosensitization of cells using clonogenic and cytotoxicity assays. Conversely, AC overexpression further decreased sensitivity to radiation. We also observed that radiation-induced AC upregulation was sufficient to create cross-resistance to chemotherapy as demonstrated by decreased sensitivity to Taxol and C6 ceramide compared to controls. Lower levels of caspase 3/7 activity were detected in cells pretreated with radiation, also indicating increased resistance. Finally, utilization of the small molecule AC inhibitor, LCL385, sensitized PPC-1 cells to radiation and significantly decreased tumor xenograft growth. These data suggest a new mechanism of cancer cell resistance to radiation, through upregulation of AC that is, in part, mediated by application of the therapy itself. An improved understanding of radiotherapy and the application of combination therapy achieved in this study offer new opportunities for the modulation of radiation effects in the treatment of cancer.

AB - Radiation resistance in a subset of prostate tumors remains a challenge to prostate cancer radiotherapy. The current study on the effects of radiation on prostate cancer cells reveals that radiation programs an unpredicted resistance mechanism by upregulating acid ceramidase (AC). Irradiated cells demonstrated limited changes of ceramide levels while elevating levels of sphingosine and sphingosine-1-phosphate. By genetically downregulating AC with small interfering RNA (siRNA), we observed radiosensitization of cells using clonogenic and cytotoxicity assays. Conversely, AC overexpression further decreased sensitivity to radiation. We also observed that radiation-induced AC upregulation was sufficient to create cross-resistance to chemotherapy as demonstrated by decreased sensitivity to Taxol and C6 ceramide compared to controls. Lower levels of caspase 3/7 activity were detected in cells pretreated with radiation, also indicating increased resistance. Finally, utilization of the small molecule AC inhibitor, LCL385, sensitized PPC-1 cells to radiation and significantly decreased tumor xenograft growth. These data suggest a new mechanism of cancer cell resistance to radiation, through upregulation of AC that is, in part, mediated by application of the therapy itself. An improved understanding of radiotherapy and the application of combination therapy achieved in this study offer new opportunities for the modulation of radiation effects in the treatment of cancer.

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ER -

Acid ceramidase upregulation in prostate cancer cells confers resistance to radiation: AC inhibition, a potential radiosensitizer

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