Inhibition of telomerase activity enhances hyperthermia-mediated radiosensitization.
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.
Agarwal
Manjula
M
Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63108, USA.
Pandita
Shruti
S
Hunt
Clayton R
CR
Gupta
Arun
A
Yue
Xuan
X
Khan
Saira
S
Pandita
Raj K
RK
Pratt
David
D
Shay
Jerry W
JW
Taylor
John-Stephen A
JS
Pandita
Tej K
TK
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
D004791:Enzyme Inhibitors; C468783:H2AX protein, human; D018840:HSP70 Heat-Shock Proteins; D006657:Histones; C422952:telomerase RNA; D012313:RNA; D019098:Telomerase