The antiapoptotic effect of IL-6 autocrine loop in a cellular model of advanced prostate cancer is mediated by Mcl-1.
Levels of the proinflammatory cytokine interleukin-6 (IL-6) are increased in therapy-resistant prostate cancer. IL-6 has been considered a positive growth factor in late-stage prostate cancer cells and a potential target for therapeutic interference. Effects of inhibition of IL-6 on cell survival were studied in LNCaP-IL6+ cells, a model system for advanced prostate cancer, which produce IL-6. We show that the autocrine IL-6 loop is responsible for resistance to apoptosis and increased cellular levels of myeloid cell leukemia-1 (Mcl-1) protein, an antiapoptotic member of the Bcl-2 family. Treatment of cells with a chimeric anti-IL-6 antibody (CNTO 328) led to the induction of apoptosis and downregulation of Mcl-1 protein levels. Specific knockdown of Mcl-1 gene expression by small interfering RNA also yielded an increase in apoptosis of LNCaP-IL-6+ cells. Vice versa, inactivation of IL-6 autocrine loop had no influence on apoptosis levels in the absence of Mcl-1, thus suggesting this molecule as a mediator of the survival action of IL-6. Mcl-1 protein regulation by the endogenous cytokine directly involved the extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase pathway. Our data support the concept of anti-IL-6 targeted therapy in therapy-resistant prostate cancer.
Cavarretta
I T
IT
Department of Urology, Innsbruck Medical University, Innsbruck, Austria.
Neuwirt
H
H
Untergasser
G
G
Moser
P L
PL
Zaki
M H
MH
Steiner
H
H
Rumpold
H
H
Fuchs
D
D
Hobisch
A
A
Nemeth
J A
JA
Culig
Z
Z
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D019898:Autocrine Communication; D018450:Disease Progression; D005419:Flavonoids / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D005419:Flavonoids; D015850:Interleukin-6; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; C504234:siltuximab