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

Abstract

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.