Induction of nitric oxide synthase-dependent telomere shortening after functional inhibition of Hsp90 in human tumor cells.
In most cancer cells, the lengths of telomeres, the functional DNA-protein complexes located at chromosome ends, are maintained by the ribonucleoprotein telomerase. Hsp90 facilitates the assembly of telomerase and remains associated with the functional complex, implying a direct involvement of Hsp90 in telomere length regulation. In an effort to elucidate the effects of Hsp90 inhibition on function and viability of human prostate cancer cells, both pharmacological (radicicol) and genetic (small interfering RNA) approaches were utilized to target Hsp90. Depletion of functional Hsp90 caused dramatic telomere shortening followed by apoptosis. Of particular significance, these cells exhibit a high level of nitric oxide synthase (NOS)-dependent free radical production, and simultaneous treatment of cells with the NOS inhibitor L-NAME resulted in telomere elongation and prevention of apoptosis. In addition, we observe significant DNA damage assessed by telomere dysfunction, although in the absence of a classical DNA damage response. Overall, our data suggest a novel mechanism whereby inhibition of Hsp90 disrupts free radical homeostasis and contributes directly to telomere erosion, further implicating Hsp90 as a potential therapeutic target for cancer cells.
Compton
Sarah A
SA
Department of Pharmacology and Toxicology, Medical College of Virginia, 1101 E. Marchall St., Richmond, VA 23298-0662, USA.
Elmore
Lynne W
LW
Haydu
Kimberly
K
Jackson-Cook
Colleen K
CK
Holt
Shawn E
SE
D001483:Base Sequence; D045744:Cell Line, Tumor; D002869:Chromosome Aberrations; D004247:DNA / Q000235:genetics; D004249:DNA Damage; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005609:Free Radicals / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007783:Lactones / Q000494:pharmacology; D018942:Macrolides; D008954:Models, Biological; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D016615:Telomere / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*
D004791:Enzyme Inhibitors; D005609:Free Radicals; D018841:HSP90 Heat-Shock Proteins; D007783:Lactones; D018942:Macrolides; D034741:RNA, Small Interfering; D004247:DNA; D019001:Nitric Oxide Synthase; C035359:monorden; D019331:NG-Nitroarginine Methyl Ester; D004121:Dimethyl Sulfoxide