Extracellular ATP activates multiple signalling pathways and potentiates growth factor-induced c-fos gene expression in MCF-7 breast cancer cells

• Published in: Carcinogenesis (New York) 2000-12, Vol.21 (12), p.2175-2181
• Main Authors: Wagstaff, S.C., Bowler, W.B., Gallagher, J.A., Hipskind, R.A.
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - analogs & derivatives; Adenosine Triphosphate - pharmacology; Adenosine Triphosphate - physiology; Anisomycin - pharmacology; Biochemistry, Molecular Biology; Biological and medical sciences; Breast Neoplasms; camp response element binding protein; Carcinogens - pharmacology; Cell physiology; CREB; EGF; epidermal growth factor; Epidermal Growth Factor - pharmacology; ERK; extracellular signal-regulated kinase; Female; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Neoplastic - drug effects; Genes, fos; Growth Substances - pharmacology; Humans; Life Sciences; Molecular and cellular biology; parathyroid hormone-related peptide; Parathyroid Hormone-Related Protein; Proteins - pharmacology; PTHrP; Signal transduction; Signal Transduction - drug effects; TCF; ternary complex factor; Tetradecanoylphorbol Acetate - pharmacology; TGFβ1; Transcription, Genetic - drug effects; Transforming Growth Factor beta - pharmacology; transforming growth factor β1; Tumor Cells, Cultured
• ISSN: 0143-3334; 1460-2180; 1460-2180
• DOI: 10.1093/carcin/21.12.2175

In the human breast cancer cell line MCF-7, the nucleotides ATPγS and UTP, acting extracellularly through the purinergic receptor P2Y2, lead to elevated intracellular calcium levels and increased proliferation. ATPγS and UTP treatment of MCF-7 cells activated transcription of the immediate early gene c-fos, an important component in the response to proliferative stimulation. c-fos induction was enhanced by co-treatment with ATPγS and a variety of proliferative agents including growth factors, tumour promoters and stress. Stimulation with ATPγS or epidermal growth factor (EGF) led to extracellular signal-regulated kinase (ERK) activation and phosphorylation of the transcription factors CREB and Elk-1. Co-stimulation synergistically activated fos expression and notably led to increased levels of ERK, CREB and EGF receptor phosphorylation, as well as hyperphosphorylation of ternary complex factor. Nevertheless, the ERK pathway does not fully account for this synergy, since fos induction was differentially sensitive to the MEK inhibitor U0126, indicating that these two agonists signal differently to this immediate early gene. Thus, extracellular nucleotides co-operate with growth factors to activate genes linked to the proliferative response in MCF-7 cells through activation of specific purinergic receptors, which thereby represent important potential targets for arresting the neoplastic progression of breast cancer cells.