Genetic inhibition of telomerase results in sensitization and recovery of breast tumor cells.
Telomerase, a ribonucleoprotein enzyme minimally composed of an RNA template (human telomerase RNA) and a catalytically active protein subunit (human telomerase reverse transcriptase), synthesizes telomeric repeats onto chromosome ends and is obligatory for continuous tumor cell proliferation. Telomerase is an attractive anticancer therapeutic target because its activity is present in >90% of human cancers, including >95% of breast carcinomas. Traditional chemotherapies lack the ability to effectively control and cure breast cancer, in part because residual cells are often resistant to DNA-damaging modalities. Although numerous telomerase inhibition strategies cause cancer cells to undergo apoptosis or senescence, there is often a lag period between the beginning of the treatment regimen and a biological effect. Thus, our goal for these studies was to show that effectively blocking telomerase genetically together with standard chemotherapeutic agents, doxorubicin/Adriamycin or Taxol, would increase the sensitization and efficacy for triggering senescence and/or apoptosis in cultures of breast cancer cells while reducing toxicity. We find that blocking telomerase in breast tumor cells substantially increases the sensitization at lower doses of Adriamycin or Taxol and that the kinetics of senescence/apoptosis is more rapid at higher concentrations. Combined with telomerase inhibition, Taxol treatment induced both apoptosis (its typical cell fate) and senescence, both at high enough levels to suggest that these two cellular responses are not mutually exclusive. Genetic inhibition of telomerase is eventually reversed due to up-regulation of endogenous telomerase activity without a net change in telomere length, suggesting that telomerase inhibition itself, not necessarily short telomeres, is important for sensitization.
Department of Human Genetics, Medical College of Virginia at Virginia Commonwealth University, Richmond, Virginia 23298-0662, USA.
Kennon R
KR
Poynter
Patrick C
PC
Sachs
A Taylor
AT
Bright
Meghan S
MS
Breed
Binh N
BN
Nguyen
Lynne W
LW
Elmore
Shawn E
SE
Holt
D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004795:Enzyme Stability / Q000187:drug effects / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D016615:Telomere / Q000187:drug effects / Q000378:metabolism
D004317:Doxorubicin; C509186:TERT protein, human; D019098:Telomerase