Far Infrared Ray Radiation Inhibits the Proliferation of A549, HSC3 and Sa3 Cancer Cells through Enhancing the Expression of ATF3 Gene

DOI: 10.4236/jemaa.2010.26050   PDF   HTML   XML   4,809 Downloads   9,314 Views   Citations


Far-infrared ray (FIR) is electromagnetic wave between 4 and 1000 μm. FIR causes heating, but how it affects cells is not well understood. In this study, we developed a culture incubator that can continuously irradiate cells with FIR and examined the effects of FIR on five human cancer cell lines, namely A431 (vulva), A549 (lung), HSC3 (tongue), MCF7 (breast) and Sa3 (gingiva). We found that FIR inhibits cell proliferation and induces cell hypertrophy without apoptosis in A549, HSC3 and Sa3 cells. Flow cytometry revealed that the inhibition of proliferation was due to G2/M arrest. Contrary, FIR did not inhibit cell proliferation and cause cell hypertrophy in A431 or MCF7 cells. Microarray analysis revealed that FIR suppressed the expression of cell proliferation-related and stress-responsive genes in FIR-sensitive cell lines (A549, HSC3 and Sa3). ATF3 in particular was identified as a key mediator of the FIR effect. Over-expression of ATF3 inhibited cell proliferation and knockdown of ATF3 mRNA using an antisense oligonucleotide suppressed FIR-induced growth arrest. These results indicate that a body temperature range of FIR radiation suppresses the proliferation of A549, HSC3, Sa3 cells and it appears that ATF3 play important roles in this effect.

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K. Yamashita, S. Dalkhsuren, T. Ishikawa, K. Sumida, J. Ishibashi, H. Hosokawa, A. Ueno, F. Nasu and S. Kitamura, "Far Infrared Ray Radiation Inhibits the Proliferation of A549, HSC3 and Sa3 Cancer Cells through Enhancing the Expression of ATF3 Gene," Journal of Electromagnetic Analysis and Applications, Vol. 2 No. 6, 2010, pp. 382-394. doi: 10.4236/jemaa.2010.26050.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Y. Udagawa, H. Nagasawa and S. Kiyokawa, “Inhibition by Whole-Body Hyperthermia with Far-Infrared Rays of the Growth of Spontaneous Mammary Tumours in Mice,” Anticancer Research, 1999, Vol. 19, No. 5B, pp. 4125- 4130.
[2] Y. Udagawa and H. Nagasawa, “Effects of Combined Treatment with Coffee Cherry and Whole-Body Hyperthermia on the Growth of Spontaneous Mammary Tumours in SHN Mice,” In Vivo, Vol. 14, No. 3, 2000, pp. 431-435.
[3] Y. Udagawa, K. Inada and H. Nagasawa, “Inhibition by Single Whole-Body Hyperthermia with Glucose Administration of the Growth of Spontaneous Mammary Tumors in Mice,” Japanese Journal of Hyperthermic Oncology, 2000, Vol. 16, No. 4, pp. 229-236.
[4] H. Nagasawa, K. Inada, H. Ishigame, S. Kusakawa and Y. Udagawa, “Different Schedules of Whole-Body Hyperthermia with or without Glucose for the Inhibition of Mammary Tumors and Uterine Adenomyosis in SHN Mice,” Bulletin of the School of Agriculture, Meiji University, No. 127, 2001, pp. 43-51.
[5] Y. Udagawa and H. Nagasawa, “Effects of Far-Infrared Ray on Reproduction, Growth, Behaviour and Some Physiological Parameters in Mice,” In Vivo, Vol. 14, No. 2, 2000, pp. 321-326.
[6] H. Nagasawa, Y. Udagawa and S. Kiyokawa, “Evidence that Irradiation of Far-Infrared Rays Inhibits Mammary Tumour Growth in SHN Mice,” Anticancer Research, Vol. 19, No. 3A, 1999, pp. 1797-1800.
[7] S. Inoue and M. Kabaya, “Biological Activities Caused by Far-Infrared Radiation,” International Journal of Biometeorology, Vol. 33, No. 3, 1989, pp. 145-150.
[8] K. Honda and S. Inoue, “Sleep-Enhancing Effects of Far-Infrared Radiation in Rats,” International Journal of Biometeorology, Vol. 32, No. 2, 1988, pp. 92-94.
[9] H. Hosokawa, K. Yamashita, J. Ishibashi, N. Ishikawa, H. Morimoto, T. Ishikawa, S. Kitamura and M. Nagayama, “A New Animal Raiser: Effect of Limited Infrared Radiation on Tumor Growth of A431 Cells,” ITE Letters, Vol. 6, No. 6, 2005, pp. 597-602.
[10] F. Teraoka, Y. Hamada and J. Takahashi, “Bamboo Charcoal Inhibits Growth of HeLa Cells in Vitro,” dental materials journal, Vol. 23, No. 4, 2004, pp. 633-637.
[11] K. Yamashita, H. Hosokawa, J. Ishibashi, N. Ishikawa, H. Morimoto, T. Ishikawa, et al., “Development of CO2 Incubator with Limited Far-Infrared Radiation for Activation of Glucose Metabolism,” ITE Letters, Vol. 6, No. 5, 2005, pp. 53-57.
[12] Y. H. Yang, S. Dudoit, P. Luu, D. M. Lin, V. Peng, J. Ngai, et al., “Normalization for cDNA Microarray Data: A Robust Composite Method Addressing Single and Multiple Slide Systematic Variation,” Nucleic Acid Research, Vol. 30, No. 4, 2002, p. e15.
[13] H. Lowry, N. J. Rosebrough, A. L. Farr and R. J. Randall, “Protein Measurement with the Folin Phenol Reagent,” Journal of Biological Chemistry, Vol. 193, No. 1, 1951, pp. 265-275.
[14] C. Zhang, J. Kawauchi, M. T. Adachi, Y. Hashimoto, S. Oshiro, T. Aso, et al., “Activation of JNK and Trans- criptional Repressor ATF3/LRF1 through the IRE1/ TRAF2 Pathway is Implicated in Human Vascular Endothelial Cell Death by Homocysteine,” Biochemical and Biophysical Research Communications, Vol. 289, No. 3, 2001, pp. 718-724.
[15] T. Hai, C. D. Wolfgang, D. K. Marsee, A. E. Allen and U. Sivaprasad, “ATF3 and Stress Responses,” Gene Expression, Vol. 7, No. 4-6, 1999, pp. 321-335.
[16] F. Fan, S. Jin, S. A. Amundson, T. Tong, W. Fan, H. Zhao, et al., “ATF3 Induction Following DNA Damage is Regulated by Distinct Signaling Pathways and Over-Expression of ATF3 Protein Suppresses Cells Growth,” Oncogene, Vol. 21, No. 49, 2002, pp. 7488-7496.
[17] J. Ishibashi, K. Yamashita, T. Ishikawa, H. Hosokawa, K. Sumida, M. Nagayama, et al., “The Effects Inhibiting the Proliferation of Cancer Cells by Far-Infrared Radiation (FIR) are Controlled by the Basal Expression Level of Heat Shock Protein (HSP) 70A,” Medical Oncology, in Press.
[18] M. C. Bonnet, R. Weil, E. Dam, A. G. Hovanessian and E. F. Meurs, “PKR Stimulates NF-kappaB Irrespective of its Kinase Function by Interacting with the IkappaB Kinase Complex,” Molecular and Cellular Biology, Vol. 20, No. 13, 2000, pp. 4532-4542
[19] O. Donzé, J. Deng, J. Curran, R. Sladek, D. Picard and N. Sonenberg, “The Protein Kinase PKR: A Molecular Clock that Sequentially Activates Survival and Death Programs,” EMBOJ, Vol. 23, No. 3, 2004, pp. 564-571
[20] G. Liang, C. D. Wolfgang, B. P. Chen, T. H. Chen and T. Hai, “ATF3 Gene,” Journal of Biological Chemistry, Vol. 271, No. 3, 1996, pp. 1695-1701.
[21] T. Hai and M. G. Hartman, “The Molecular Biology and Nomenclature of the Activating Transcription Factor/ cAMP Responsive Element Binding Family of Transcription Factors: Activating Transcription Factor Proteins and Homeostasis,” Gene, Vol. 273, No. 1, 2001, pp. 1-11.
[22] B. P. Chen, C. D. Wolfgang and T. Hai, “Analysis of ATF3: A Transcription Factor Induced by Physiological Stresses and Modulated by gadd153/Chop10,” Molecular and Cellular Biology, Vol. 16, No. 3, 1996, pp. 1157- 1168.
[23] S. Guerra, L. A. Lopez-Fernandez, M. A. Garcia, A. Zaballos and M. Esteban, “Human Gene Profiling in Response to the Active Protein Kinase, Interferon-Induced Serine/Threonine Protein Kinase (PKR), in Infected Cells. Involvement of the Transcription Factor ATF-3 IN PKR-Induced Apoptosis,” Journal of Biological Chemistry, Vol. 281, No. 27, 2006, pp. 18734-18742.
[24] K. Tamura, B. Hua, S. Adachi, I. Guney, J. Kawauchi, M. Morioka, et al., “Stress Response Gene ATF3 is a Target of c-myc in Serum-Induced Cell Proliferation,” EMBO Journal, Vol. 24, No. 14, 2005, pp. 2590-2601.
[25] K. Yamaguchi, S. H. Lee, J. S. Kim, J. Wimalasena, S. Kitajima and S. J. Baek, “Activating Transcription Factor 3 and Early Growth Response 1 are the Novel Targets of LY294002 in a Phosphatidylinositol 3-Kinase-Indepen- dent Pathway,” Cancer Research, Vol. 66, No. 4, 2006, pp. 2376-2384.
[26] T. Nawa, M. T. Nawa, M. T. Adachi, I. Uchimura, R. Shimokawa, K. Fujisawa, et al., “Expression of Transcriptional Repressor ATF3/LRF1 in Human Atherosclerosis: Colocalization and Possible Involvement in Cell Death of Vascular Endothelial Cells,” Atherosclerosis 2002, Vol. 161, No. 2, pp. 281-291.
[27] Y. Okamoto, et al., “Transgenic Mice with Cardiac-speci- fic Expression of Activating Transcription Factor 3, a Stress-Inducible Gene, have Conduction Abnormalities and Contractile Dysfunction,” American Journal of Pathology, Vol. 159, No. 2, 2001, pp. 639-650.
[28] G. Liang, C. D. Wolfgang, B. P. Cheng, T. H. Cheng and T. Hai, “ATF3 Gene,” Journal of Biological Chemistry, Vol. 271, No. 3, 1996, pp. 1695-1701.
[29] M. R. Thompson, D. K. Xu, et al., “ATF3 Transcription Factor and its Emerging Roles in Immunity and Cancer,” Journal of Molecular Medicine, Vol. 87, No. 11, 2009, pp. 1053-1060.
[30] F. G. Bottone, Jr, J. M. Martinez, J. B. Collins, C. A. Afshari and T. E. Eling, “Gene Modulation by the Cyclooxygenase Inhibitor, Sulindac Sulfide, in Human Colorectal Carcinoma Cells: Possible Link to Apoptosis,” Journal of Molecular Medicine, Vol. 278, No. 28, 2003, pp. 25790-25801.
[31] V. Syed, K. Mukherjee, J. Lyons-Weiler, K.-M. Lau, T. Mashima, T. Tsuruo and S.-M. Ho, “Identification of ATF-3, Caveolin-1, DLC-1 and NM23-H2 as Putative Antitumorigenic, Progesterone-Regulated Genes for Ovarian Cancer Cells by Gene Profiling,” Oncogene, Vol. 24, No. 10, 2005, pp. 1774-1787.
[32] C. Yan, S. Jamaluddin, B. Aggarwal, J. Myers and D. Douglas, “Gene Expression Profiling Identifies Activating Transcription Factor 3 as a Novel Contributor to the Proapoptotic Effect of Curcumin,” Molecular Cancer Therapeutics, Vol. 4, No. 2, 2005, pp. 233-241.
[33] S. J. Baek, J. S. Kim, F. R. Jackson, T. E. Eling, M. F. McEntee and S. H. Lee, “Epicatechin Gallate-Induced Expression of NAG-1 is Associated with Growth Inhibition and Apoptosis in Colon Cancer Cells,” Carcinogenesis, 2004, Vol. 25, No. 12, pp. 2425-2432.
[34] E. Allen-Jennings, M. G. Hartman, G. J. Kociba and T. Hai, “The Roles of ATF3 in Glucose Homeostasis. A transgenic Mouse Model with Liver Dysfunction and Defects in Endocrine Pancreas,” Journal of Biological Chemistry, Vol. 276, No. 31, 2001, pp. 29507-29514.
[35] T. Ishigiro, H. Nagawa, et al., “Inhibitory Effect of ATF3 Antisense Oligonucleotide on Ectopic Growth of HT29 Human Colon Cancer Cells,” Japanese Journal of Cancer Research, Vol. 91, No. 8, 2000, pp. 833-836.
[36] T. Mashima, S. Udagawa and T. Tsuruo, “Involvement of Transcriptional Repressor ATF3 in Acceleration of Caspase Protease Activation during DNA Damaging Agent- Induced Apoptosis,” Journal of Cellular Physiology, Vol. 188, No. 3, 2001, pp. 352-358.
[37] C. D. Wolfgang, B. P. Chen, J. L. Martindale, N. J. Holbrook and T. Hai, “gadd153/Chop10, a Potential Target Gene of the Transcriptional Repressor ATF3,” Molecular Cell Biology, Vol. 17, No. 11, 1997, pp. 6700-6707.
[38] J. C. Hsu, T. Laz, K. L. Mohn and R. Tau, “Identification of LRF-1, a Leucine-Zipper Protein that is Rapidly and Highly Induced in Regenerating Liver,” Proceedings of the National Academy Sciences U S A, Vol. 88, No. 9, 1991, pp. 3511-515.
[39] K. Nobori, H. Ito, M. Tamamori-Adachi, S. Adachi, Y. Ono, J. Kawauchi, S. Kitajima, F. Marumo and M. Isobe, “ATF3 Inhibits Doxorubicin-Induced Apoptosis in Cardiac Myocytes: A Novel Cardioprotective Role of ATF3,” Journal of Molecular and Cellular Cardiology, Vol. 34, No. 10, 2002, pp. 1387-1397.
[40] J. Kawauchi, C. Zhang, K. Nobori, Y. Hashimoto, M. T. Adachi, A. Noda, et al., “Transcriptional Repressor Activating Transcription Factor 3 Protects Human Umbilical Vein Endothelial Cells from Tumor Necrosis Factor-Al- pha-Induced Apoptosis through Down-Regulation of p53 Transcription,” Journal of Biology Chemistry, 2002, Vol. 277, No. 41, pp. 39025-39034.
[41] G. Brawerman, “mRNA Decay: Finding the Right Targets,” Cell, Vol. 57, No. 1, 1989, pp. 9-10.
[42] C. A. Beelman and R. Parker, “Degradation of mRNA in Eukaryotes,” Cell, Vol. 81, No. 2, 1995, pp. 179-183.
[43] B. P. Chen, G. Liang, J. Whelan and T. Hai, “ATF3 and ATF3 yZip. Transcriptional Repression Versus Activation by Alternatively Spliced Isoforms,” Journal of Biological Chemistry, Vol. 269, No. 22, 1994, pp. 15819- 15826.
[44] S. Perez, E. Vial, H. Van Damm and M. Castallazzi, “Transcription Factor ATF3 Partially Transforms Chick Embryo Fibroblasts by Promoting Growth Factor-Inde- pendent Proliferation,” Oncogene, 2001, Vol. 20, No. 9, pp. 1135-1141.
[45] T. Nawa, M. T. Nawa, Y. Cai, C. Zhang, I. Uchimura, S. Narumi, F. Numano and S. Kitajima, ”Repression of TNF-Alpha-Induced E-Selectin Expression by PPAR Activators: Involvement of Transcriptional Repressor LRF-1/ ATF3,” Biochemical and Biophysical Research Communication, Vol. 275, No. 2, 2000, pp. 406-411.
[46] C. Yan, H. Wang and D. D. Boyd, “ATF3 Represses 72-kDa Type IV Collagenase (MMP-2) Expression by Antagonizing p53-Dependent Trans-Activation of the Collagenase Promoter,” Journal of Biology Chemistry, Vol. 277, No. 13, 2002, pp. 10804-10812.
[47] T. Hai, “The ATF Transcription Factors in Cellular Adaptive Responses,” In: J. Ma, Ed., Gene Expression and Regulation, Higher Education Press, Beijing, 2006, pp. 322-333.
[48] D. Lu, C. D. Wolfgang and T. Hai, “Activating Trans- cription Factor 3, a Stress-Inducible Gene, Suppresses Ras-Stimulated Tumorigenesis,” Journal of Biology Che- mistry, Vol. 281, No. 15, 2006, pp. 10473-1048.
[49] M. Matsumoto, M. Minami, K. Takeda, Y. Sakao and S. Akira, “Ectopic Expression of CHOP (GADD153) Induces Apoptosis in M1 Myeloblastic Leukemia Cells,” FEBS Letters, Vol. 395, No. 2-3, 1996, pp. 143-147.
[50] K. Tamura, B. Hua, S. Adachi, I. Guney, J. Kawauchi, M. Morioka, M. Tamamori-Adachi, Y. Tanaka, Y. Nakabe- ppu, M. Sunamori, J. Sedivy and S. Kitajima, “Stress Response Gene ATF3 is a Target of c-myc in Serum-In- duced Cell Proliferation,” The EMBO Journal, Vol. 24, 2005, pp. 2590-2601.
[51] X. Yin, J. W. DeWille and T. Hai, “A Potential Dichotomous Role of ATF3, an Adaptive-Response Gene, in Cancer Development,” Oncogene, Vol. 27, No. 15, 2008, pp. 2118-2127.
[52] T. Ishiguro, M. Nakajima, M. Naito, T. Muto and T. Tsuruo, “Identification of Genes Differentially Expressed in B16 Murine Melanoma Sublines with Different Metastatic Potentials,” Cancer Research, 1996, Vol. 56, pp. 875-879.
[53] M. Janz, M. Hummel, M. Truss, B. Wollert-Wulf, S. Mathas, K. Jöhrens, C. Hagemeier, K. Bommert, H. Stein, D. Dörken and R. C. Bargou, “Classical Hodgkin Lymphoma is Characterized by High Constitutive Expression of Activating Transcription Factor 3 (ATF3), Which Pro- motes Viability of Hodgkin/Reed-Sternberg Cells,” Blood, Vol. 107, 2006, pp. 2536-2539.

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