Genes and pathways downstream of telomerase in melanoma metastasis

doi:10.1073/pnas.0510085103

Genes and pathways downstream of telomerase in melanoma metastasis

*Auerback Melanoma Research Laboratory, Cutaneous Oncology Program, Comprehensive Cancer Center, and Department of Dermatology, University of California, San Francisco, CA 94115;
Departments of ^‡Biochemistry and Biophysics and
^¶Epidemiology and Biostatistics, University of California, San Francisco, CA 94143;
^§California Pacific Medical Research Institute, San Francisco, CA 94115;
^‖Department of Urology and Comprehensive Cancer Center, University of California, San Francisco, CA 94115; and
**Department of Pathology and Comprehensive Cancer Center Tissue Core, University of California, San Francisco, CA 94115

Edited by Arthur B. Pardee, Dana–Farber Cancer Institute, Boston, MA, and approved June 2, 2006
↵ ^†S.B. and M.N. contributed equally to this work. (received for review November 22, 2005)

Abstract

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.

Footnotes

^††To whom correspondence should be addressed at:
Comprehensive Cancer Center, University of California, 1600 Divisadero Street, Second Floor, Box 1706, San Francisco, CA 94115.
E-mail: kashanim{at}derm.ucsf.edu
Author contributions: E.H.B. and M.K.-S. designed research; S.B., M.N., S.L., S. Fong, S.T., and J.R. performed research; R.R.L., F.L.B., J.E.C., C.H., R.J.D., and E.H.B. contributed new reagents/analytic tools; S.B., M.N., S.L., S. Fong, S.T., D.H.M., S. Federman, F.L.B., R.W.S., J.E.C., C.H., R.J.D., E.H.B., and M.K.-S. analyzed data; and S.B., R.J.D., E.H.B., and M.K.-S. wrote the paper.
Conflict of interest statement: No conflicts declared.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

Abbreviations:

TER,

telomerase RNA;

TER 180 Rz,

ribozyme targeting mouse TER at position 180.