Cellular and gene expression responses involved in the rapid growth inhibition of human cancer cells by RNA interference-mediated depletion of telomerase RNA.
Inhibition of the up-regulated telomerase activity in cancer cells has previously been shown to slow cell growth but only after prior telomere shortening. Previously, we have reported that, unexpectedly, a hairpin short interfering RNA specifically targeting human telomerase RNA rapidly inhibits the growth of human cancer cells independently of p53 or telomere length and without bulk telomere shortening (Li, S., Rosenberg, J. E., Donjacour, A. A., Botchkina, I. L., Hom, Y. K., Cunha, G. R., and Blackburn, E. H. (2004) Cancer Res. 64, 4833-4840). Here we have demonstrated that such telomerase RNA knockdown in cancer cells does not cause telomere uncapping but rather induces changes in the global gene expression profile indicative of a novel response pathway, which includes suppression of specific genes implicated in angiogenesis and metastasis, and is distinct from the expression profile changes induced by telomere-uncapping mutant template telomerase RNAs. These cellular responses to depleting telomerase in human cancer cells together suggest that cancer cells are "telomerase-addicted" and uncover functions of telomerase in tumor growth and progression in addition to telomere maintenance.
Li
Shang
S
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, California 94143, USA.
Crothers
Julia
J
Haqq
Christopher M
CM
Blackburn
Elizabeth H
EH
D001483:Base Sequence; D002455:Cell Division / Q000235:genetics*; D045744:Cell Line, Tumor; D056767:Cyclin G2; D016213:Cyclins / Q000235:genetics; D004249:DNA Damage; D020869:Gene Expression Profiling; D006801:Humans; D034622:RNA Interference; D012334:RNA, Neoplasm / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics; D019098:Telomerase / Q000235:genetics*; D016615:Telomere
C101593:CCNG2 protein, human; D056767:Cyclin G2; D016213:Cyclins; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D019098:Telomerase