, Volume 14, Issue 5, pp 721–728 | Cite as

Local hyperthermia induces apoptosis of keratinocytes in both normal skin and condyloma acuminata via different pathways

  • Xiaoqin Wang
  • Xing-Hua GaoEmail author
  • Xiaodong Li
  • Yuxiao Hong
  • Ruiqun Qi
  • Hong-Duo Chen
  • Li Zhang
  • Huachen Wei
Original Paper


Local hyperthermia has been successfully used in the treatment of viral warts. However, the mechanism of action of hyperthermia has largely remained unclear. In this study we evaluated the effect of local hyperthermia on the induction of apoptosis in human keratinocytes, and expression of apoptosis-related genes in both condyloma acuminata (CA) and normal skin. The study showed that higher hyperthermia increased the number of apoptotic keratinocytes in CA and normal skin. The temperature-dependent increased expression of Fas and Bax were observed in both CA and normal skin. In contrast, the expression of Bcl-2 in CA was decreased at both transcriptional and translational levels. Furthermore, the transcriptional expression of DR4 and DR5 were increased in a temperature-dependent manner in CA, but not in normal skin. These results suggest that different mechanisms of action might be involved in hyperthermia induced apoptosis in CA and normal skin.


Hyperthermia Apoptosis Condyloma acuminata Skin 



Condyloma acuminata


Human papillomavirus


Tumor necrosis factor




Death domains


Death receptor


Phosphate buffered solution


Tumor necrosis factor-related apoptosis-inducing ligand


Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling





This study was supported by National Science Foundation (30740082), Program for New Century Excellent Talents in University (NCEP-04-0287) and Program for Changjiang Scholars and Innovative Research Team in University (IRT0760), Ministry of Education.

The authors declare that they have no conflict of interest.


  1. 1.
    Koutsky L (1997) Epidemiology of genital human papillomavirus infection. Am J Med 102:3–8. doi: 10.1016/S0002-9343(97)00177-0 CrossRefPubMedGoogle Scholar
  2. 2.
    Maw RD, Reitano M, Roy M (1998) An international survey of patients with genital warts: perceptions regarding treatment and impact on lifestyle. Int J STD AIDS 9:571–578. doi: 10.1258/0956462981921143 CrossRefPubMedGoogle Scholar
  3. 3.
    Kodner CM, Nasraty S (2004) Management of genital warts. Am Fam Physician 70:2335–2342PubMedGoogle Scholar
  4. 4.
    Wust P, Hildebrandt B (2002) Hyperthermia in combined treatment of cancer. Lancet Oncol 3:487–497. doi: 10.1016/S1470-2045(02)00818-5 CrossRefPubMedGoogle Scholar
  5. 5.
    Harmon BV, Corder AM, Collins RJ et al (1990) Cell death induced in a murine mastocytoma by 42–47°C heating in vitro: evidence that the form of death changes from apoptosis to necrosis above a critical heat load. Int J Radiat Biol 58:845–858. doi: 10.1080/09553009014552221 CrossRefPubMedGoogle Scholar
  6. 6.
    Sakaguchi Y, Stephens LC, Makino M et al (1995) Apoptosis in tumors and normal tissues induced by whole body hyperthermia in rats. Cancer Res 55:5459–5464PubMedGoogle Scholar
  7. 7.
    Stern P, Levine N (1992) Controlled localized heat therapy in cutaneous warts. Arch Dermatol 128(7):945–948. doi: 10.1001/archderm.128.7.945 CrossRefPubMedGoogle Scholar
  8. 8.
    Pfau A, Abd-el-Raheem TA, Baumler W et al (1994) Nd:YAG laser hyperthermia in the treatment of recalcitrant verrucae vulgares (Regensburg’s technique). Acta Derm Venereol 74(3):212–214PubMedGoogle Scholar
  9. 9.
    El-Tonsy MH, Anbar TE, El-Domyati M et al (1999) Density of viral particles in pre and post Nd: YAG laser hyperthermia therapy and cryotherapy in plantar warts. Int J Dermatol 38(5):393–398. doi: 10.1046/j.1365-4362.1999.00719.x CrossRefPubMedGoogle Scholar
  10. 10.
    Werness BA, Levine AJ, Howley PM (1990) Association of human papillomavirus types 16 and 18 E6 proteins with p53. Science 248:76–79. doi: 10.1126/science.2157286 CrossRefPubMedGoogle Scholar
  11. 11.
    Garnett T, Filippova M, Duerksen-Hughes PJ (2006) Accelerated degradation of FADD and procaspase 8 in cells expressing human papilloma virus 16 E6 impairs TRAIL-mediated apoptosis. Cell Death Differ 13(11):1915–1926. doi: 10.1038/sj.cdd.4401886 CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Filippova M, Parkhurst L, Duerksen-Hughes PJ (2004) The human papillomavirus 16 E6 protein binds to Fas associated death domain and protects from Fas-triggered apoptosis. J Biol Chem 279:25729–25744. doi: 10.1074/jbc.M401172200 CrossRefPubMedGoogle Scholar
  13. 13.
    Kabsch K, Mossadegh N, Kohl A et al (2004) The HPV-16 E5 protein inhibits TRAIL- and FasL-mediated apoptosis in human keratinocyte raft cultures. Intervirology 47:48–56. doi: 10.1159/000076642 CrossRefPubMedGoogle Scholar
  14. 14.
    Kabsch K, Alonso A (2002) The human papillomavirus type 16 E5 protein impairs TRAIL- and FasL mediated apoptosis in HaCaT cells by different mechanisms. J Virol 76:12162–12172. doi: 10.1128/JVI.76.23.12162-12172.2002 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Sima N, Wang W, Kong D et al (2008) RNA interference against HPV16 E7 oncogene leads to viral E6 and E7 suppression in cervical cancer cells and apoptosis via upregulation of Rb and p53. Apoptosis 13(2):273–281. doi: 10.1007/s10495-007-0163-8 CrossRefPubMedGoogle Scholar
  16. 16.
    Singh M, Singh N (2008) Induction of apoptosis by hydrogen peroxide in HPV 16 positive human cervical cancer cells: involvement of mitochondrial pathway. Mol Cell Biochem 310(1–2):57–65. doi: 10.1007/s11010-007-9665-5 CrossRefPubMedGoogle Scholar
  17. 17.
    Tjalma WA, Weyler JJ, Bogers JJ et al (2001) The importance of biological factors (bcl-2, bax, p53, PCNA, MI, HPV and angiogenesis) in invasive cervical cancer. Eur J Obstet Gynecol Reprod Biol 97:223–230. doi: 10.1016/S0301-2115(00)00541-8 CrossRefPubMedGoogle Scholar
  18. 18.
    Wiley SR, Schooley K, Smolak PJ et al (1995) Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity 3:673–682. doi: 10.1016/1074-7613(95)90057-8 CrossRefPubMedGoogle Scholar
  19. 19.
    Pan G, Rourke KO, Chinnaiyan AM et al (1997) The receptor for the cytotoxic ligand TRAIL. Science 276:111–113. doi: 10.1126/science.276.5309.111 CrossRefPubMedGoogle Scholar
  20. 20.
    Ostberg JR, Kabingu E, Repasky EA (2003) Thermal regulation of dendritic cell activation and migration from skin explants. Int J Hyperthermia 19:520–533. doi: 10.1080/02656730310001607986 CrossRefPubMedGoogle Scholar
  21. 21.
    Van den Brule AJ, Meijer CJ, Bakels V et al (1990) Rapid detection of human papillomavirus in cervical scrapes by combined general primer-mediated and type-specific polymerase chain reaction. J Clin Microbiol 28(12):2739–2743PubMedPubMedCentralGoogle Scholar
  22. 22.
    Ni X, Hazarika P, Zhang C et al (2001) Fas ligand expression by neoplastic T lymphocytes mediates elimination of CD8 + cytotoxic T lymphocytes in mycosis fungoides: a potential mechanism of tumor immune escape? Clin Cancer Res 7(9):2682–2692PubMedGoogle Scholar
  23. 23.
    Hildebrandt B, Hegewisch-Becker S, Kerner T et al (2005) Current status of radiant whole-body hyperthermia at temperatures >41.5 degrees C and practical guidelines for the treatment of adults. The German interdisciplinary working group on hyperthermia. Int J Hyperthermia 21(2):169–183. doi: 10.1080/02656730400003401 CrossRefPubMedGoogle Scholar
  24. 24.
    Hildebrandt B, Wust P, Ahlers O et al (2002) The cellular and molecular basis of hyperthermia. Crit Rev Oncol Hematol 43:33–56. doi: 10.1016/S1040-8428(01)00179-2 CrossRefPubMedGoogle Scholar
  25. 25.
    Blaha M, Kohl J, Dubose D et al (2001) Ultrastructural and histological effects of exposure to CEES or heat in a human epidermal model. In Vitro Mol Toxicol 14:15–23. doi: 10.1089/109793301316882513 CrossRefGoogle Scholar
  26. 26.
    Matylevitch NP, Schuschereba ST, Mata JR et al (1998) Apoptosis and accidental cell death in culture human keratinocytes after thermal injury. Am J Pathol 153:567–577CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Schieke SM, Schroeder P, Krutmann J (2003) Cutaneous effects of infrared radiation: from clinical observations to molecular response mechanisms. Photodermatol Photoimmunol Photomed 19:228–234. doi: 10.1034/j.1600-0781.2003.00054.x CrossRefPubMedGoogle Scholar
  28. 28.
    Tamada Y, Takama H, Kitamura T et al (1994) Identification of programmed cell death in normal human skin tissues by using specific labeling of fragmented DNA. Br J Dermatol 131:521–524CrossRefPubMedGoogle Scholar
  29. 29.
    Boehm I (2006) Apoptosis in physiological and pathological skin: implications for therapy. Curr Mol Med 6:375–394. doi: 10.2174/156652406777435390 CrossRefPubMedGoogle Scholar
  30. 30.
    Kulms D, Zeise E, Poppelmann B et al (2002) DNA damage, death receptor activation and reactive oxygen species contribute to ultraviolet radiation-induced apoptosis in an essential and independent way. Oncogen 21:5844–5851. doi: 10.1038/sj.onc.1205743 CrossRefGoogle Scholar
  31. 31.
    Leverkus M, Yaar M, Gilchrist BA (1997) Fas/Fas ligand interaction contribute to UV-induced apoptosis in human keratinocytes. Exp Cell Res 232:255–262. doi: 10.1006/excr.1997.3514 CrossRefPubMedGoogle Scholar
  32. 32.
    Salah-Eldin AE, Inoue S, Tsukamoto S et al (2003) An association of Bcl-2 phosphorylation and Bax localization with their functions after hyperthermia and paclitaxel treatment. Int J Cancer 103:53–60. doi: 10.1002/ijc.10782 CrossRefPubMedGoogle Scholar
  33. 33.
    Moody CA, Fradet-Turcotte A, Archambault J et al (2007) Human papillomaviruses activate caspases upon epithelial differentiation to induce viral genome amplification. Proc Natl Acad Sci USA 104:19541–19546. doi: 10.1073/pnas.0707947104 CrossRefPubMedGoogle Scholar
  34. 34.
    Tollefson AE, Hermiston TW, Lichtenstein DL et al (1998) Forced degradation of Fas inhibits apoptosis in adenovirus-infected cells. Nature 392:726–730. doi: 10.1038/33712 CrossRefPubMedGoogle Scholar
  35. 35.
    Albert ML, Sauter B, Bhardwaj N (1998) Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs. Nature 392:86–89. doi: 10.1038/32183 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Xiaoqin Wang
    • 1
    • 2
  • Xing-Hua Gao
    • 1
    Email author
  • Xiaodong Li
    • 1
  • Yuxiao Hong
    • 1
  • Ruiqun Qi
    • 1
  • Hong-Duo Chen
    • 1
  • Li Zhang
    • 1
  • Huachen Wei
    • 1
    • 3
  1. 1.Department of DermatologyNo. 1 Hospital of China Medical UniversityShenyangChina
  2. 2.Department of DermatologyShengjing Hospital of China Medical UniversityShenyangChina
  3. 3.Department of DermatologyMount Sinai Medical CenterNew YorkUSA

Personalised recommendations