Rosiglitazone enhances the radiosensitivity of p53-mutant HT-29 human colorectal cancer cells.
Combined-modality treatment has improved the outcome in cases of various solid tumors, and radiosensitizers are used to enhance the radiotherapeutic efficiency. Rosiglitazone, a synthetic ligand of peroxisome proliferator-activated receptors gamma used in the treatment of type-2 diabetes, has been shown to reduce tumor growth and metastasis in human cancer cells, and may have the potential to be used as a radiosensitizer in radiotherapy for human colorectal cancer cells. In this study, rosiglitazone treatment significantly reduced the cell viability of p53-wild type HCT116 cells but not p53-mutant HT-29 cells. Interestingly, rosiglitazone pretreatment enhanced radiosensitivity in p53-mutant HT-29 cells but not HCT116 cells, and prolonged radiation-induced G(2)/M arrest and enhanced radiation-induced cell growth inhibition in HT-29 cells. Pretreatment with rosiglitazone also suppressed radiation-induced H2AX phosphorylation in response to DNA damage and AKT activation for cell survival; on the contrary, rosiglitazone pretreatment enhanced radiation-induced caspase-8, -9, and -3 activation and PARP cleavage in HT-29 cells. In addition, pretreatment with a pan-caspase inhibitor, zVAD-fmk, attenuated the levels of caspase-3 activation and PARP cleavage in radiation-exposed cancer cells in combination with rosiglitazone pretreatment. Our results provide proof for the first time that rosiglitazone suppresses radiation-induced survival signals and DNA damage response, and enhances the radiation-induced apoptosis signaling cascade. These findings can assist in the development of rosiglitazone as a novel radiosensitizer.
Chiu
Shu-Jun
SJ
Department of Life Science, Tzu Chi University, Hualien, Taiwan. chiusj@mail.tcu.edu.tw
Hsaio
Ching-Hui
CH
Tseng
Ho-Hsing
HH
Su
Yu-Han
YH
Shih
Wen-Ling
WL
Lee
Jeng-Woei
JW
Chuah
Jennifer Qiu-Yu
JQ
D017209:Apoptosis; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000532:radiotherapy*; D003131:Combined Modality Therapy; D019073:HT29 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D010766:Phosphorylation; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011836:Radiation Tolerance / Q000187:drug effects* / Q000235:genetics; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000627:therapeutic use*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
C468783:H2AX protein, human; D006657:Histones; D011838:Radiation-Sensitizing Agents; D045162:Thiazolidinediones; D016159:Tumor Suppressor Protein p53; D000077154:Rosiglitazone; D011065:Poly(ADP-ribose) Polymerases; D051057:Proto-Oncogene Proteins c-akt