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Prostate tumor cells with cancer progenitor properties have high telomerase activity and are rapidly killed by telomerase interference
Author(s) -
Xu Tong,
He Kaijie,
Wang Lina,
Goldkorn Amir
Publication year - 2011
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.21355
Subject(s) - telomerase , cancer research , telomerase reverse transcriptase , prostate cancer , biology , clonogenic assay , telomere , progenitor cell , cancer , cancer cell , rna interference , ectopic expression , cell culture , stem cell , microbiology and biotechnology , gene , rna , genetics
Abstract BACKGROUND Cancer progenitor cells (CPCs) have been postulated to promote treatment resistance and disease progression in prostate and other malignancies. We investigated whether the enzyme telomerase, which is active in cancer cells and in normal stem cells, plays an important role in CPC which can be exploited to neutralize these cells. METHODS We used flow cytometry and assays of gene expression, clonogenicity, and invasiveness to isolate and characterize a putative CPC subpopulation from freshly resected human prostatectomy specimens. Telomerase activity was measured by qPCR‐based Telomeric Repeat Amplification Protocol (TRAP). Telomerase interference was achieved by ectopic expression of a mutated telomerase RNA construct which reprograms telomerase to generate “toxic” uncapped telomeres. Treated cells were assayed for apoptosis, proliferation in culture, and xenograft tumor formation. RESULTS CPC in prostate tumors expressed elevated levels of genes associated with a progenitor phenotype and were highly clonogenic and invasive. Significantly, CPC telomerase activity was 20‐ to 200‐fold higher than in non‐CPC from the same tumors, and CPC were exquisitely sensitive to telomerase interference which induced rapid apoptosis and growth inhibition. Similarly, induction of telomerase interference in highly tumorigenic CPC isolated from a prostate cancer cell line abrogated their ability to form tumor xenografts. CONCLUSIONS Human prostate tumors contain a CPC subpopulation with markedly elevated telomerase activity which renders them acutely susceptible to telomerase interference. These findings offer the first tumor‐derived and in vivo evidence that telomerase may constitute a CPC “Achilles heel” which may ultimately form the basis for more effective new CPC‐targeting therapies. Prostate 71:1390–1400, 2011. © 2011 Wiley‐Liss, Inc.