JCT  Vol.2 No.4 , October 2011
Par-4 Sensitizes Human Colon Cancer Cells to Chemoradiotherapy
Abstract: Despite aggressive treatment and recent advances, cancers of the colon and rectum remain a leading cause of death worldwide. In the case of rectal cancer, chemo-radiotherapy (CRT) is given prior to surgery to provide a greater chance of sphincter sparing surgery and lower the incidence of local recurrence. However, toxicity of CRT remains a problem. The tumor suppressor, Par-4, serves to sensitize tumor cells to chemotherapy and radiation therapy. This study tested the effects of increased Par-4 expression in HT29 human colon cancer cells. The results show the success of Par-4 in sensitizing the tumor cells to both radiation and chemo therapies. In addition, the presence of increased Par-4 caused a positive response to lower doses of both therapies. This supports the idea that Par-4 may be a viable target for gene therapy in cancer treatment, particularly in the case of accessible tumors such as rectal cancers, serving to reduce the required doses of CRT, and consequent side effects, for a successful treatment of rectal cancer.
Cite this paper: nullD. Contract, H. Mackley and R. Irby, "Par-4 Sensitizes Human Colon Cancer Cells to Chemoradiotherapy," Journal of Cancer Therapy, Vol. 2 No. 4, 2011, pp. 542-547. doi: 10.4236/jct.2011.24074.

[1]   American Cancer Society, “Cancer Facts and Figures 2010,” 2010.

[2]   Gastrointestinal Tumor Study Group, “Prolongation of the Disease-Free Interval in Surgically Treated Rectal Carcinoma,” The New England Journal of Medicine, Vol. 312, No. 23, 1985, pp. 1465-1472. doi:10.1056/NEJM198506063122301

[3]   Medical Research Council Rectal Cancer Working Party, “Randomised Trial of Surgery Alone versus Radiotherapy Followed by Surgery for Potentially Operable Locally Advanced Rectal Cancer,” Lancet, Vol. 348, No. 9042, 1996, pp. 1605-1610. doi:10.1016/S0140-6736(96)05348-2

[4]   S. F. Sells, D. P. Wood Jr., S. S. Joshi-Barve, S. Muthukumar, R. J. Jacob, S. A. Crist, et al., “Commonality of the Gene Programs Induced by Effectors of Apoptosis in Androgen-Dependent and -Independent Prostate Cells,” Cell Growth & Differentiation, Vol. 5, No. 4, 1994, pp. 457-466.

[5]   N. El-Guendy and V. M. Rangnekar, “Apoptosis by Par-4 in Cancer and Neurodegenerative Diseases,” Experimental Cell Research, Vol. 283, No. 1, 2003, pp. 51-66. doi:10.1016/S0014-4827(02)00016-2

[6]   R. Burikhanov, Y. Zhao, A. Goswami, S. Qiu, S. R. Schwarze and V. M. Rangnekar, “The Tumor Suppressor Par-4 Activates an Extrinsic Pathway for Apoptosis,” Cell, Vol. 138, No. 2, 2009, pp. 377-388. doi:10.1016/j.cell.2009.05.022

[7]   C. L. Kline, S. S. Shanmugavelandy, M. Kester and R. B. Irby, “Delivery of Par-4 Plasmid in Vivo Via Nanoliposomes Sensitizes Colon Tumor Cells Subcutaneously Implanted into Nude Mice to 5-Fu,” Cancer Biology & Therapy, Vol. 8, No. 19, 2009, pp. 1831-1837. doi:10.4161/cbt.8.19.9592

[8]   S. Boehrer, D. Nowak, E. Puccetti, M. Ruthardt, N. Sattler, B. Trepohl, et al., “Prostate-Apoptosis-Response-Gene-4 Increases Sensitivity to Trail-Induced Apoptosis,” Leukemia Research, Vol. 30, No. 5, 2006, pp. 597-605.

[9]   J. Cook, S. Krishnan, S. Ananth, S. F. Sells, Y. Shi, M. M. Walther, et al., “Decreased Expression of the Pro-Apoptotic Protein Par-4 in Renal Cell Carcinoma,” Oncogene, Vol. 18, No. 5, 1999, pp. 1205-1208. doi:10.1038/sj.onc.1202416

[10]   S. F. Sells, S. S. Han, S. Muthukkumar, N. Maddiwar, R. Johnstone, E. Boghaert, et al., “Expression and Function of the Leucine Zipper Protein Par-4 in Apoptosis,” Molecular and Cellular Biology, Vol. 17, No. 7, 1997, pp. 3823-3832.

[11]   M. M. Shareef, N. Cui, R. Burikhanov, S. Gupta, S. Satishkumar, S. Shajahan, et al., “Role of Tumor Necrosis Factor-Alpha and Trail in High-Dose Radiation-Induced Bystander Signaling in Lung Adenocarcinoma,” Cancer Research, Vol. 67, No. 24, 2007, pp. 11811-11820.

[12]   M. Barradas, A. Monjas, M. T. Diaz-Meco, M. Serrano and J. Moscat, “The Downregulation of the Pro-Apoptotic Protein Par-4 Is Critical for Ras-Induced Survival and Tumor Progression,” The EMBO Journal, Vol. 18, No. 1999, pp. 6362-6369.

[13]   G. Moreno-Bueno, P. J. Fernandez-Marcos, M. Collado, M. J. Tendero, S. M. Rodriguez-Pinilla, I. Garcia-Cao, et al., “Inactivation of the Candidate Tumor Suppressor Par-4 in Endometrial Cancer,” Cancer Research, Vol. 67, No. 5, 2007, pp. 1927-1934. doi:10.1158/0008-5472.CAN-06-2687

[14]   M. M. Ahmed, D. Sheldon, M. A. Fruitwala, K. Venkatasubbarao, E. Y. Lee, S. Gupta, et al., “Downregulation of Par-4, a Pro-Apoptotic Gene, in Pancreatic Tumors Harboring K-Ras Mutation,” International Journal of Cancer, Vol. 122, No. 1, 2008, pp. 63-70. doi:10.1002/ijc.23019

[15]   S. Vetterkind, M. Boosen, K. H. Scheidtmann and U. Preuss, “Ectopic Expression of Par-4 Leads to Induction of Apoptosis in Cns Tumor Cell Lines,” International Journal of Oncology, Vol. 26, No. 1, 2005, pp. 159-167.

[16]   A. K. Sharma, C. L. Kline, A. Berg, S. Amin and R. B. Irby, “The Akt Inhibitor Isc-4 Activates Prostate Apoptosis Response Protein-4 and Reduces Colon Tumor Growth in a Nude Mouse Model,” Clinical Cancer Research, Vol. 17, No. 13, 2011, pp. 4474-4483.