Molecular parameters of hyperthermia for radiosensitization.
Hyperthermia is a potent sensitizer of cell killing by ionizing radiation (IR), however, the precise mechanism of heat-induced cell death is not yet clear. Radiosensitization can be attributed to the fact that heat is a pleiotropic damaging agent, affecting multiple cell components to varying degrees by altering protein structures, thus influencing the DNA damage response. Hyperthermia alone induces several steps associated with IR signaling in cells. For example, hyperthermia enhances ATM kinase activity and increases cellular ATM autophosphorylation. This prior activation of ATM or other components of the IR-induced signaling pathway by heat interferes with the normal IR-induced signaling required for chromosomal DNA double-strand break repair, thus resulting in increased cell killing post irradiation. Hyperthermia also induces heat shock protein 70 (HSP70) synthesis and enhances telomerase activity. HSP70 expression is associated with radioresistance. Inactivation of HSP70 and telomerase increases residual DNA DSBs post IR exposure, which correlates with increased cell killing, supporting the role of HSP70 and telomerase in IR-induced DNA damage repair. Thus, hyperthermia influences several molecular parameters involved in sensitizing tumor cells to radiation and can enhance the potential of targeted radiotherapy.
Pandita
Tej K
TK
Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri 63108, USA. pandita@wustl.edu
Pandita
Shruti
S
Bhaumik
Sukesh R
SR
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics*; D018869:Heat-Shock Response / Q000235:genetics*; D006657:Histones / Q000378:metabolism; D006801:Humans; D006979:Hyperthermia, Induced; D009369:Neoplasms / Q000378:metabolism / Q000532:radiotherapy*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011836:Radiation Tolerance / Q000235:genetics / Q000502:physiology*; D019098:Telomerase / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C468783:H2AX protein, human; D018840:HSP70 Heat-Shock Proteins; D006657:Histones; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; C509186:TERT protein, human; D019098:Telomerase