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Interplay between the intracellular energy sensor AMP-activated protein kinase (AMPK) and the estrogen receptor activities in regulating rat pituitary tumor cell (GH3) growth in vitro

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Abstract

Estrogen receptor α has a role in regulating rat somatolactotroph tumor cell growth (GH3 cells). AMP-activated protein kinase (AMPK) is a metabolic checkpoint which is able to negatively regulate intracellular signaling downstream of growth factors receptors in conditions increasing cellular AMP levels. We have recently reported on the role of AMPK activation in affecting viability and proliferation of GH3 cells. In the present study, we investigated the interplay between ER- and AMPK-pathways. Results can be regarded as relevant to the development of novel multi-targeted pharmacological therapies against pituitary tumors. We confirmed that estradiol (E2) and the ER antagonist fulvestrant exert stimulatory and inhibitory effects, respectively on GH3 cell growth in a competitive manner. The upstream kinase LKB1 is known to phosphorylate and activate AMPK. Here we showed that neither E2 nor fulvestrant caused a downregulation of LKB1 expression and phospho-AMPK levels in GH3 cells. Actually, fulvestrant strongly reduced the phosphorylation of ACC, which is a direct target of AMPK and a known index of AMPK activity. 2-deoxyglucose, a compound reducing glucose utilization, caused an increase in AMPK activity vs baseline and was able to hinder the stimulatory effect of E2 on cell viability, confirming that the exposure of GH3 cells to estrogens does not prevent them from being responsive to the inhibitory activity of compounds activating AMPK. Finally, the AMPK activator AICAR (AMP analog) did not cause further decrease in cell viability in the course of co-treatments with fulvestrant versus fulvestrant alone, in agreement with impaired phospho-AMPK activity in the presence of the anti-estrogen.

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Acknowledgments

This work was supported by local funds (2011–2012) from the University of Brescia to G. T. and D. C and funds from the Center for Research in Osteoporosis and Bone Metabolism, University of Brescia (A. G.).

Conflict of interest

L. F., A. C., D. C. and G. T. have nothing to disclose. M. S is employed by Novartis Farma SpA, (Origgio, Italy) and A. G. has received consulting and lecture fees form Ipsen, Novartis and Pfeizer.

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Authors and Affiliations

  1. Unit of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123, Brescia, Italy

    Giovanni Tulipano, Lara Faggi, Andrea Cacciamali & Daniela Cocchi

  2. Department of Clinical and Experimental Medicine, University of Brescia, Brescia, Italy

    Andrea Giustina

  3. Novartis Farma, Origgio, Va, Italy

    Maurizio Spinello

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  1. Giovanni Tulipano
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  2. Lara Faggi
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  3. Andrea Cacciamali
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  4. Maurizio Spinello
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  5. Daniela Cocchi
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  6. Andrea Giustina
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Correspondence to Giovanni Tulipano.

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Tulipano, G., Faggi, L., Cacciamali, A. et al. Interplay between the intracellular energy sensor AMP-activated protein kinase (AMPK) and the estrogen receptor activities in regulating rat pituitary tumor cell (GH3) growth in vitro. Pituitary 17, 203–209 (2014). https://doi.org/10.1007/s11102-013-0488-y

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  • DOI: https://doi.org/10.1007/s11102-013-0488-y

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