The signalling pathway for BCG-induced interleukin-6 production in human bladder cancer cells.
Intravesical bacillus Calmette-Guerin (BCG) is currently the therapy of choice for superficial bladder cancer with a 60-70% response rate. Induction of cytokine production (e.g. IL-6, etc.) by BCG has been found in patient's urine in vivo as well as bladder cancer cell lines. However, the signalling mechanisms are still unclear. In this study, we investigated the effect of BCG on cAMP production and its role in regulating interleukin-6 expression in the human bladder cancer cell line, MGH. After 1 hr exposure to BCG, IL-6 gene expression in MGH cells increased by 2.5-3-fold and cAMP production increased by 8-10-fold in a time- and dose-dependent manner. BCG-induced cAMP production was inhibited by both antifibronectin antibody and an adenylate cyclase inhibitor, SQ22536 in a dose-dependent way. In the presence of SQ22536, IL-6 expression in MGH cells was also greatly reduced. Furthermore, cAMP-dependent kinase inhibitors H7 and HA1004 also inhibited BCG-induced IL-6 expression in MGH, with HA1004 being much less effective than H7. Thus, BCG induces cAMP production and may regulate interleukin-6 expression partially via a cAMP-dependent pathway in human bladder cancer cells.
Zhang
Ye
Y
Department of Biochemistry, National University of Singapore, 10 Kent Ridge Crescent, 119260, Singapore, Singapore.
Mahendran
Ratha
R
Yap
Lai Lai
LL
Esuvaranathan
Kesavan
K
Khoo
Hoon Eng
HE
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000494:pharmacology; D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D001500:BCG Vaccine / Q000276:immunology / Q000494:pharmacology*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011489:Protein Denaturation; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D013449:Sulfonamides; D013997:Time Factors; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000378:metabolism*
D000906:Antibodies; D001500:BCG Vaccine; D004791:Enzyme Inhibitors; D007093:Imidazoles; D015850:Interleukin-6; D007546:Isoquinolines; D010726:Phosphodiesterase Inhibitors; D012333:RNA, Messenger; D013449:Sulfonamides; C048819:4-(3,4-dibutoxybenzyl)-2-imidazolidinone; C017759:9-(tetrahydro-2-furyl)-adenine; D005576:Colforsin; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; C043204:N-(2-guanidinoethyl)-5-isoquinolinesulfonamide; D000242:Cyclic AMP; D000225:Adenine