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.

Triple negative breast cancer development can be selectively suppressed by sustaining an elevated level of cellular cyclic AMP through simultaneously blocking its efflux and decomposition

“…In this study, we showed that high concentration of cAMP analog 8-Br-cAMP (> 1 mM) specifically suppressed TNBC cell growth (Figure 1A). This finding is in agreement with an early report in which 8-Br-cAMP was shown to inhibit growth of TNBC MDA-MB-231 cells at a concentration above 1mM [21]. Since it is infeasible to use almost any agent at such high dose in clinic, we tested the potential of adenylate cyclase activator forskolin and PDE inhibitor IBMX as an alternative.…”

“…A recent study reported that various cAMP-elevating agents were able to inhibit growth of MDA-MB-231, a TNBC line [21]. To determine if the same could be generalized to other breast cancer cell lines, we examined the effect of 8-Br-cAMP, a PDE-resistant cAMP analog, on growth of 4 TNBC and 4 ER+ cell lines.…”

Leptin inhibits proliferation of breast cancer cells at supraphysiological concentrations by inhibiting mitogen-activated protein kinase signaling

“…In a study aiming to potentiate the antitumor effects of cAMP-agonists, leptin induced apoptosis in MDA-MB-231 breast cancer cells when cAMP levels were increased (22), which resulted in ERK1/2 inactivation and the subsequent inhibition of protein kinase A (PKA) expression (23). Thus, at supraphysiological concentrations, leptin may not require elevated cAMP levels to decrease PKA, and this may provide a mechanism for the effects observed in our study.…”

The Pharmacological and Physiological Role of Multidrug-Resistant Protein 4

“…In macrophages, cAMP elevation induced p27 kip1 , increased complexes between cyclin D1 and CDK4, impaired the activating T172-phosphorylation of CDK4 by CDK-activating kinase, and caused G1 phase arrest (Kato et al, 1994). Also, it was demonstrated that an increase in intracellular cAMP prevented cell cycle progression from the G1 phase to the S phase in breast cancer (Naviglio et al, 2009), vascular smooth muscle cells , and lymphoma cells (Zambon et al, 2005). Concordantly, MRP4 blockade led to cell cycle arrest at the G1 phase in cell lines of lung cancer, neuroblastoma, pancreatic cancer, and AML where MRP4 was overexpressed.…”