Interferon alpha down-regulates telomerase reverse transcriptase and telomerase activity in human malignant and nonmalignant hematopoietic cells.
Recently, the derepressed expression of the catalytic subunit of telomerase, human telomerase reverse transcriptase (hTERT), the enzyme that elongates telomeres, has been implicated as an important step in the immortalization process. The exact regulation of hTERT expression, which is the rate-limiting factor for telomerase activity, is at present unclear. As transformed cells seem to be dependent on a constitutive telomerase activity, the availability of inhibitors would potentially be of great value in antineoplastic therapy. Interferons (IFNs) have been successfully used in the treatment of several forms of malignancies, but the underlying molecular mechanisms responsible for the antitumor activity are poorly defined. In this study we have investigated the effects of IFNs on hTERT expression and telomerase activity. We found that IFN-alpha rapidly (commonly within 4 hours) and significantly down-regulates the expression of hTERT and telomerase activity in a number of human malignant hematopoietic cell lines, primary leukemic cells from patients with acute leukemia as well as T-lymphocytes from healthy donors. This effect of IFN-alpha did not seem to depend on IFN-alpha-mediated cell growth arrest or alterations in c-myc expression. The finding that IFN induces a repression of hTERT and a decrease in telomerase activity suggests a novel mechanism that may play a significant role in the antitumor action of IFN. (Blood. 2000;96:4313-4318)
Xu
D
D
Department of Medicine, Division of Hematology and Department of Oncology-Pathology, Radiumhemmet Karolinska Hospital, Stockholm, Sweden.
Erickson
S
S
Szeps
M
M
Gruber
A
A
Sangfelt
O
O
Einhorn
S
S
Pisa
P
P
Grandér
D
D
D000208:Acute Disease; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002051:Burkitt Lymphoma / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D003513:Cycloheximide / Q000494:pharmacology; D004261:DNA Replication / Q000187:drug effects; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004268:DNA-Binding Proteins; D003864:Depression, Chemical; D004790:Enzyme Induction / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology*; D007951:Leukemia, Myeloid / Q000473:pathology; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000473:pathology; D016410:Lymphoma, T-Cell, Cutaneous / Q000473:pathology; D009101:Multiple Myeloma / Q000473:pathology; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012313:RNA; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D011994:Recombinant Proteins; D013601:T-Lymphocytes / Q000187:drug effects* / Q000201:enzymology; D019098:Telomerase / Q000096:biosynthesis* / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D009363:Neoplasm Proteins; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011994:Recombinant Proteins; C422952:telomerase RNA; D012313:RNA; D003513:Cycloheximide; D019098:Telomerase