title: Inhibition of epidermal growth factor-induced cell transformation and Akt activation by caffeine.
abstract: We found that caffeine significantly inhibited epidermal growth factor (EGF)- and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced cell transformation in the JB6 mouse epidermal cell line. The tumor promoter-induced cell transformation was also blocked by treatment with an adenosine A1 receptor antagonist, 8-phenyltheophylline (8-PTH). Caffeine slightly attenuated activation of EGF-induced activator protein 1 (AP-1) activation, which play important roles in cell transformation, but only at the highest concentration examined (1 mM). Interestingly, pretreatment with caffeine suppressed EGF-induced phosphorylation and activation of Akt and ribosomal p 70 S6 protein kinase (p 70 S 6 K), a target of Akt, without inhibiting phosphatidylinositol 3-kinase (PI 3 K) activation. The inhibition of Akt activation of caffeine was not a result of its adenosine receptor antagonism. Because Akt plays a key role in signal transduction pathways leading to cell proliferation and apoptosis, our results provide novel insight into possible mechanisms of the chemotherapeutic effect of caffeine.
authors.affiliation: Department of Hospital Pharmacy, School of Medicine, Kanazawa University, Kanazawa, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Nomura
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ichimatsu
authors.forename: Shuzo
authors.initials: S
authors.lastname: Moritani
authors.forename: Ichiko
authors.initials: I
authors.lastname: Koyama
authors.forename: Zigang
authors.initials: Z
authors.lastname: Dong
authors.forename: Koichi
authors.initials: K
authors.lastname: Yokogawa
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Miyamoto
mesh_terms: D000818:Animals; D002110:Caffeine / Q000494:pharmacology*; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced* / Q000473:pathology*; D000242:Cyclic AMP / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D058915:Purinergic P1 Receptor Antagonists; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D002110:Caffeine; D000242:Cyclic AMP; D004815:Epidermal Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D058915:Purinergic P1 Receptor Antagonists; D013806:Theophylline; D018808:Transcription Factor AP-1; C028322:8-phenyltheophylline