Cytokines modulate telomerase activity in a human multiple myeloma cell line.
Telomerase is a ribonucleoprotein DNA polymerase that elongates the telomeres of chromosomes to compensate for losses that occur with each round of DNA replication and maintain chromosomal stability. Interleukin 6 (IL-6) and insulin-like growth factor 1 (IGF-1) are proliferative and survival factors for human multiple myeloma (MM) cells. To date, however, the effects of IGF-1 and IL-6 on telomerase activity and associated sequelae in MM cells have not been characterized. In this study, we evaluated the effects of IGF-1 and IL-6 on telomerase activity in MM cell lines (MM.1S, U266, and RPMI 8226), as well as patient MM cells. We show that these cytokines up-regulate telomerase activity without alteration of human telomerase reverse transcriptase (hTERT) protein expression. We also demonstrate that increased telomerase activity triggered by these cytokines is mediated by phosphatidylinositol 3'-kinase (PI3k)/Akt/nuclear factor kappaB (NFkappaB) signaling. We confirm involvement of PI3k/Akt/NFkappaB signaling because the PI3k inhibitors wortmannin and LY294002 or the inhibitor of NFkappaB (IkappaB) kinase inhibitor PS-1145 block constitutive and cytokine-induced up-regulation of telomerase activity. Furthermore, we show that dexamethasone (Dex) reduces telomerase activity through the inhibition of hTERT expression before the induction of apoptosis. Importantly, IGF-1 and IL-6 abrogate Dex-induced down-regulation of telomerase activity and apoptosis. The protective effect of those cytokines against Dex-induced down-regulation of telomerase activity is blocked by both wortmannin and PS-1145, whereas the protection against Dex-induced apoptosis is blocked by wortmannin but not PS-1145. Therefore, our results demonstrate that telomerase activity is related not only to transcriptional regulation of hTERT by NFkappaB but also to posttranscriptional regulation because of phosphorylation of hTERT by Akt kinase. These studies therefore demonstrate that telomerase activity is associated with cell growth, survival, and drug resistance in MM cells.
Akiyama
Masaharu
M
Jerome Lipper Multiple Myeloma Center, Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Hideshima
Teru
T
Hayashi
Toshiaki
T
Tai
Yu-Tzu
YT
Mitsiades
Constantine S
CS
Mitsiades
Nicholas
N
Chauhan
Dharminder
D
Richardson
Paul
P
Munshi
Nikhil C
NC
Anderson
Kenneth C
KC
D017209:Apoptosis / Q000187:drug effects; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004268:DNA-Binding Proteins; D003907:Dexamethasone / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology*; D009101:Multiple Myeloma / Q000201:enzymology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D019098:Telomerase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects
D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D003907:Dexamethasone; D019098:Telomerase