Genes and pathways downstream of telomerase in melanoma metastasis.
Recent studies have demonstrated a role for telomerase in driving tumor progression, but its mechanism of action remains unclear. Here we show that stable, ribozyme-mediated suppression of mouse telomerase RNA reduced telomerase RNA expression, telomerase activity, and telomere length, which significantly reduced tumor invasion and metastatic potential. Our studies reveal that previously unidentified effects of telomerase may mediate its tumor-promoting effects. First, reducing telomerase activity induced a more dendritic morphology, accompanied by increased melanin content and increased expression of tyrosinase, a key enzyme in melanin biosynthesis. Second, gene expression profiling revealed that telomerase targeting down-regulated expression of several glycolytic pathway genes, with a corresponding decrease in glucose consumption and lactate production. Thus, telomerase activity controls the glycolytic pathway, potentially altering the energy state of tumor cells and thereby modulating tyrosinase activity and melanin production. These studies have important implications for understanding the mechanisms by which telomerase promotes tumor invasion and metastasis.
Bagheri
Sepideh
S
Auerback Melanoma Research Laboratory, Cutaneous Oncology Program, Comprehensive Cancer Center, University of California, San Francisco, CA 94115, USA.
Nosrati
Mehdi
M
Li
Shang
S
Fong
Sylvia
S
Torabian
Sima
S
Rangel
Javier
J
Moore
Dan H
DH
Federman
Scot
S
Laposa
Rebecca R
RR
Baehner
Frederick L
FL
Sagebiel
Richard W
RW
Cleaver
James E
JE
Haqq
Christopher
C
Debs
Robert J
RJ
Blackburn
Elizabeth H
EH
Kashani-Sabet
Mohammed
M
D000818:Animals; D002454:Cell Differentiation; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005947:Glucose / Q000378:metabolism; D007773:Lactates / Q000378:metabolism; D008543:Melanins / Q000378:metabolism; D008545:Melanoma / Q000235:genetics* / Q000473:pathology*; D008546:Melanoma, Experimental; D051379:Mice; D008810:Mice, Inbred C57BL; D014442:Monophenol Monooxygenase / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D019098:Telomerase / Q000378:metabolism / Q000502:physiology*
D007773:Lactates; D008543:Melanins; D014442:Monophenol Monooxygenase; D019098:Telomerase; D005947:Glucose