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Research Paper

Leptin enhances growth inhibition by cAMP elevating agents through apoptosis of MDA-MB-231 breast cancer cells

Silvio Naviglio, Davide Di Gesto, Annunziata Sorrentino, Fausto Illiano, Luca Sorvillo, Alberto Abbruzzese, Monica Marra, Michele Caraglia, Emilio Chiosi, Annamaria Spina and Gennaro Illiano

Elevation of cAMP inhibits the proliferation and expression of transformed phenotype in
several cell types, including breast cancer cells. Leptin has been shown to act as a mitogen/survival
factor in many types of cancer cells. In the present work, we have studied the impact of cAMP
elevation on leptin-induced proliferation of breast cancer cells. Here we report that treatment of
estrogen receptor negative human breast cancer cell line MDA-MB-231 with leptin or cAMP
elevating agents has positive and negative effects on cell proliferation, respectively. Surprisingly,
we find that leptin strongly potentiates the anti-proliferative action of cAMP elevating agents, by
concurring to cell cycle arrest at G1 phase and inducing apoptosis. Pretreatment with the PKA
inhibitor KT-5720 completely prevented the anti-proliferative effects induced by the combination
between leptin and cAMP elevating agents. The above anti-proliferative effects were paralleled by
the decrease of cyclin D1 and A and by the increase of inhibitor p27kip1 cell cycle regulating
protein levels. In these conditions we found also a strong decrease of anti-apopotic Bcl2 protein
levels. Altogether, our data extend the evidence of adenylate cyclase/cAMP/PKA as a growth
suppressor system and of leptin as a growth promoting factor in breast cancer cells. Remarkably,
our results suggest that when cAMP levels are increased, leptin drives cells towards apoptosis, and
that targeting both cAMP levels and leptin signalling might represent a simple novel way for
therapeutic intervention in breast cancer.

Authors

Silvio Naviglio Corresponding author: silvio.naviglio@unina2.it

Department of Biochemistry and Biophysics, Second University of Naples, Medical School, Via L. De Crecchio 7, 80138 Naples, Italy

Davide Di Gesto

Department of Biochemistry and Biophysics, Second University of Naples, Medical School, Via L. De Crecchio 7, 80138 Naples, Italy

Annunziata Sorrentino

Department of Biochemistry and Biophysics, Second University of Naples, Medical School, Via L. De Crecchio 7, 80138 Naples, Italy

Fausto Illiano

Department of Biochemistry and Biophysics, Second University of Naples, Medical School, Via L. De Crecchio 7, 80138 Naples, Italy

Luca Sorvillo

Department of Biochemistry and Biophysics, Second University of Naples, Medical School, Via L. De Crecchio 7, 80138 Naples, Italy

Alberto Abbruzzese

Department of Biochemistry and Biophysics, Second University of Naples, Italy.

Monica Marra

Department of Biochemistry and Biophysics, Second University of Naples, Medical School, Via L. De Crecchio 7, 80138 Naples, Italy

Michele Caraglia Corresponding author: michele.caraglia@unina2.it

Department of Biochemistry and Biophysics “F. Cedrangolo”, Second University of Naples, Naples, Italy

Emilio Chiosi

Department of Biochemistry and Biophysics, Second University of Naples, Medical School, Via L. De Crecchio 7, 80138 Naples, Italy

Annamaria Spina

Department of Biochemistry and Biophysics, Second University of Naples, Medical School, Via L. De Crecchio 7, 80138 Naples, Italy

Gennaro Illiano

Department of Biochemistry and Biophysics, Second University of Naples, Medical School, Via L. De Crecchio 7, 80138 Naples, Italy