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Proton induces apoptosis of hypoxic tumor cells by the p53-dependent and p38/JNK MAPK signaling pathways.
Int J Oncol. 2008 Dec; 33(6):1247-56.IJ

Abstract

Tumor hypoxia is a main obstacle for radiation therapy. To investigate whether exposure to a proton beam can overcome radioresistance in hypoxic tumor cells, three kinds of cancer cells, Lewis lung carcinoma (LLC) cells, hepatoma HepG2 and Molt-4 leukemia cells, were treated with a proton beam (35 MeV, 1, 2, 5, 10 Gy) in the presence or absence of hypoxia. Cell death rates were determined 72 h after irradiation. Hypoxic cells exposed to the proton beam underwent a typical apoptotic program, showing condensed nuclei, fragmented DNA ladders, and poly-ADP-ribose polymerase (PARP) cleavage. Fluorescence-activated cell sorter analysis revealed a significant increase in Annexin-V-positive cells. Cells treated with the proton beam and hypoxia displayed increased expression of p53, p21 and Bax, but decreased levels of phospho-Rb, Bcl-2 and XIAP, as well as activated caspase-9 and -3. The proton beam with hypoxia induced cell death in wild-type HCT116 cells, but not in a p53 knockout cell line, demonstrating a requirement for p53. As reactive oxygen species (ROS) were also significantly increased, apoptosis could also be abolished by treatment with the anti-oxidant N-acetyl cysteine (NAC). P38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) were activated by the treatment, and their respective DN mutants restored the cell death induced by either proton therapy alone or with hypoxia. In conclusion, proton beam treatment did not differently regulate cancer cell apoptosis either in normoxic or hypoxic conditions via a p53-dependent mechanism and by the activation of p38/JNK MAPK pathways through ROS.

Authors+Show Affiliations

School of Life Sciences and Biotechnology, College of Natural Sciences, Kyungpook National University, Daegu 702-701, Korea.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

19020758

Citation

Lee, Kheun Byeol, et al. "Proton Induces Apoptosis of Hypoxic Tumor Cells By the P53-dependent and p38/JNK MAPK Signaling Pathways." International Journal of Oncology, vol. 33, no. 6, 2008, pp. 1247-56.
Lee KB, Kim KR, Huh TL, et al. Proton induces apoptosis of hypoxic tumor cells by the p53-dependent and p38/JNK MAPK signaling pathways. Int J Oncol. 2008;33(6):1247-56.
Lee, K. B., Kim, K. R., Huh, T. L., & Lee, Y. M. (2008). Proton induces apoptosis of hypoxic tumor cells by the p53-dependent and p38/JNK MAPK signaling pathways. International Journal of Oncology, 33(6), 1247-56.
Lee KB, et al. Proton Induces Apoptosis of Hypoxic Tumor Cells By the P53-dependent and p38/JNK MAPK Signaling Pathways. Int J Oncol. 2008;33(6):1247-56. PubMed PMID: 19020758.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Proton induces apoptosis of hypoxic tumor cells by the p53-dependent and p38/JNK MAPK signaling pathways. AU - Lee,Kheun Byeol, AU - Kim,Kye-Ryung, AU - Huh,Tae-Lin, AU - Lee,You Mie, PY - 2008/11/21/pubmed PY - 2009/2/3/medline PY - 2008/11/21/entrez SP - 1247 EP - 56 JF - International journal of oncology JO - Int J Oncol VL - 33 IS - 6 N2 - Tumor hypoxia is a main obstacle for radiation therapy. To investigate whether exposure to a proton beam can overcome radioresistance in hypoxic tumor cells, three kinds of cancer cells, Lewis lung carcinoma (LLC) cells, hepatoma HepG2 and Molt-4 leukemia cells, were treated with a proton beam (35 MeV, 1, 2, 5, 10 Gy) in the presence or absence of hypoxia. Cell death rates were determined 72 h after irradiation. Hypoxic cells exposed to the proton beam underwent a typical apoptotic program, showing condensed nuclei, fragmented DNA ladders, and poly-ADP-ribose polymerase (PARP) cleavage. Fluorescence-activated cell sorter analysis revealed a significant increase in Annexin-V-positive cells. Cells treated with the proton beam and hypoxia displayed increased expression of p53, p21 and Bax, but decreased levels of phospho-Rb, Bcl-2 and XIAP, as well as activated caspase-9 and -3. The proton beam with hypoxia induced cell death in wild-type HCT116 cells, but not in a p53 knockout cell line, demonstrating a requirement for p53. As reactive oxygen species (ROS) were also significantly increased, apoptosis could also be abolished by treatment with the anti-oxidant N-acetyl cysteine (NAC). P38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) were activated by the treatment, and their respective DN mutants restored the cell death induced by either proton therapy alone or with hypoxia. In conclusion, proton beam treatment did not differently regulate cancer cell apoptosis either in normoxic or hypoxic conditions via a p53-dependent mechanism and by the activation of p38/JNK MAPK pathways through ROS. SN - 1019-6439 UR - https://www.unboundmedicine.com/medline/citation/19020758/Proton_induces_apoptosis_of_hypoxic_tumor_cells_by_the_p53_dependent_and_p38/JNK_MAPK_signaling_pathways_ L2 - http://www.spandidos-publications.com/ijo/33/6/1247 DB - PRIME DP - Unbound Medicine ER -