title: Inhibition of telomerase activity enhances hyperthermia-mediated radiosensitization.
abstract: Hyperthermia is a potent sensitizer of cell killing by ionizing radiation (IR); however, hyperthermia also induces heat shock protein 70 (HSP70) synthesis and HSP70 expression is associated with radioresistance. Because HSP70 interacts with the telomerase complex and expression of the telomerase catalytic unit (hTERT) extends the life span of the human cells, we determined if heat shock influences telomerase activity and whether telomerase inhibition enhances heat-mediated IR-induced cell killing. In the present study, we show that moderate hyperthermia (43 degrees C) enhances telomerase activity. Inhibition of telomerase activity with human telomerase RNA-targeted antisense agents, and in particular GRN163L, results in enhanced hyperthermia-mediated IR-induced cell killing, and ectopic expression of catalytic unit of telomerase (TERT) decreased hyperthermia-mediated IR-induced cell killing. The increased cell killing by heat and IR exposure in telomerase-inhibited cells correlates with delayed appearance and disappearance of gamma-H2AX foci as well as decreased chromosome repair. These results suggest that inactivation of telomerase before combined hyperthermia and radiotherapy could improve tumor killing.
authors.affiliation: Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63108, USA.
authors.forename: Manjula
authors.initials: M
authors.lastname: Agarwal
authors.forename: Shruti
authors.initials: S
authors.lastname: Pandita
authors.forename: Clayton R
authors.initials: CR
authors.lastname: Hunt
authors.forename: Arun
authors.initials: A
authors.lastname: Gupta
authors.forename: Xuan
authors.initials: X
authors.lastname: Yue
authors.forename: Saira
authors.initials: S
authors.lastname: Khan
authors.forename: Raj K
authors.initials: RK
authors.lastname: Pandita
authors.forename: David
authors.initials: D
authors.lastname: Pratt
authors.forename: Jerry W
authors.initials: JW
authors.lastname: Shay
authors.forename: John-Stephen A
authors.initials: JS
authors.lastname: Taylor
authors.forename: Tej K
authors.initials: TK
authors.lastname: Pandita
mesh_terms: D000818:Animals; D016923:Cell Death / Q000235:genetics; D002470:Cell Survival; D002478:Cells, Cultured; D017024:Chemotherapy, Adjuvant; D003131:Combined Modality Therapy; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006657:Histones / Q000378:metabolism; D006358:Hot Temperature; D006801:Humans; D006979:Hyperthermia, Induced; D051379:Mice; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D012313:RNA / Q000235:genetics; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000235:genetics; D014410:Tumor Stem Cell Assay
chemical_list: D004791:Enzyme Inhibitors; C468783:H2AX protein, human; D018840:HSP70 Heat-Shock Proteins; D006657:Histones; C422952:telomerase RNA; D012313:RNA; D019098:Telomerase