Telomere dysfunction is related to the intrinsic radio-resistance of human oral cancer cells.
Evidence from telomerase-deficient mice strongly suggests that dysfunctional short telomeres affect cellular radio-sensitivity but this idea has yet to be extensively tested in relevant human cancer types such as oral squamous cell carcinomas (OSCCs), which are frequently treated by radiotherapy. The OSCC line BICR7 has low levels of telomerase activity, short telomeres and high levels of telomere dysfunction (judged by a high level of anaphase bridges); whereas the BICR6 line has high levels of telomerase and is more radio-resistant. Ectopic expression of the human TElomerase Reverse Transcriptase (hTERT) reduced telomere dysfunction and increased radio-resistance in BICR7 cells, but not BICR6. Furthermore, the radio-resistance of GM847 cells, which use telomerase-independent mechanisms of telomere maintenance, and of telomerase-negative normal human fibroblasts with long telomeres are similarly unaffected by ectopic expression of telomerase. We tested whether telomere function, as measured by the Anaphase Bridge Index (ABI), was found to be a useful predictor of radio-resistance in a panel of OSCC lines. Using inverse regression analysis, we found a strong inverse relationship between the ABI and radio-resistance (P<0.001), as measured by the Surviving Fraction at 4Gy (SF4). These results suggest that telomerase inhibitors could sensitise a subset of oral SCCs with short telomeres to radiotherapy and for the first time demonstrate that the tumour ABI may assist the selection of cancers that would be suitable for such sensitisation therapy.
McCaul
James A
JA
Beatson Institute for Cancer Research, Cancer Research UK Beatson Laboratories, Garscube Estate, Switchback Rd., Bearsden, Glasgow G61 1BD, UK.
Gordon
Katrina E
KE
Minty
Fay
F
Fleming
Janis
J
Parkinson
E Kenneth
EK
D000705:Anaphase; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000473:pathology* / Q000532:radiotherapy; D045744:Cell Line, Tumor; D002470:Cell Survival; D016922:Cellular Senescence; D005720:Gamma Rays; D006801:Humans; D009062:Mouth Neoplasms / Q000201:enzymology / Q000473:pathology* / Q000532:radiotherapy; D011836:Radiation Tolerance; D012044:Regression Analysis; D018709:Statistics, Nonparametric; D019098:Telomerase / Q000378:metabolism; D016615:Telomere / Q000648:ultrastructure*; D017211:Treatment Failure
D019098:Telomerase