Targeting the leptin receptor: a potential new mode of treatment for breast cancer

Breast cancer is one of the most common malignancies and a major cause of cancer death among women worldwide. The high mortality rate associated with breast cancer is mainly due to a propensity of the tumor to metastasize, even if small or undetectable. Given the relevant role of leptin in breast cancer growth and metastasis, novel strategies to counteract biological effects of this obesity-linked cytokine are warranted. Recently, we demonstrated that in MDA-MB-231 breast cancer cells, intracellular cAMP elevation completely abrogates both ERK1/2 and STAT3 phosphorylation in response to leptin. Very surprisingly, this provided evidence that when cAMP levels are increased, leptin drives cells towards apoptosis associated with a marked decrease of Bcl2 protein levels and accompanied by down-regulation of protein kinase A (PKA). The aim of the current study was to investigate the role of cAMP in leptin-associated motility of breast cancer cells. Here we show that cAMP elevation completely prevents leptin-induced migration of MDA-MB-231 breast cancer cells. Interestingly, the inhibition by cAMP-elevating agents of leptin-mediated cell migration is accompanied by a strong decrease of β3 integrin subunit and focal adhesion kinase (FAK) protein levels. Analysis of the underlying cAMP-dependent molecular mechanisms revealed that PKA blockers partly counteract the inhibition of leptin-induced migration and completely prevent the antiproliferative action by cAMP elevation. Moreover, a cAMP analogue that specifically activates Epac and not PKA has an inhibitory effect on leptin-induced cell migration as well. The present study confirms initial evidence for the efficacy of cAMP elevation against oncogenic effects of leptin, identifies β3 integrin subunit and FAK as proteins strongly down-regulated by cAMP elevation, and suggests that both cAMP/PKA- and cAMP/Epac-dependent pathways are involved in inhibition of leptin-induced migration of MDA-MB-231 breast cancer cells. The potential clinical significance and therapeutic applications of our data are discussed.

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“…42 However, novel strategies to suppress leptin signaling and counteract its biological effects are warranted.…”

Section: Discussionmentioning

confidence: 99%

cAMP Elevation Down-Regulates β3 Integrin and Focal Adhesion Kinase and Inhibits Leptin-Induced Migration of MDA-MB-231 Breast Cancer Cells

Spina

Maiolo

Esposito

et al. 2012

BioResearch Open Access

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“…The design, development and efficacy of Allo-aca in vitro and in vivo have been reported by us before [35,38-40]. An unrelated peptide Chex1-Arg20: H-Chex-Arg-Pro-Asp-Lys-Pro-Arg-Pro-Tyr-Leu-Pro-Arg-Pro-Arg-Pro-Pro-Arg-Pro-Val-Arg-NH 2 was used as control [37].…”

Section: Methodsmentioning

confidence: 99%

Exploring Leptin Antagonism in Ophthalmic Cell Models

et al. 2013

Self Cite

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BackgroundEmerging evidence suggests that angiogenic and pro-inflammatory cytokine leptin might be implicated in ocular neovascularization. However, the potential of inhibiting leptin function in ophthalmic cells has never been explored. Here we assessed mitogenic, angiogenic, and signaling leptin activities in retinal and corneal endothelial cells and examined the capability of a specific leptin receptor (ObR) antagonist, Allo-aca, to inhibit these functions.Methods and ResultsThe experiments were carried out in monkey retinal (RF/6A) and bovine corneal (BCE) endothelial cells. Leptin at 50-250 ng/mL stimulated the growth of both cell lines in a dose-dependent manner. The maximal mitogenic response (35±7 and 27±3% in RF6A and BCE cells, respectively) was noted at 24 h of 250 ng/mL leptin treatments. Leptin-dependent proliferation was reduced to base levels with 10 and 100 nM Allo-aca in BCE and RF6A cells, respectively. In both cell lines, leptin promoted angiogenic responses, with the maximal increase in tube formation (163±10 and 133±8% in RF6A and BCE cultures, respectively) observed under a 250 ng/mL leptin treatment for 3 h. Furthermore, in both cell lines 250 ng/mL leptin modulated the activity or expression of several signaling molecules involved in proliferation, inflammatory activity and angiogenesis, such as STAT3, Akt, and ERK1/2, COX2, and NFκB. In both cell lines, leptin-induced angiogenic and signaling responses were significantly inhibited with 100 nM Allo-aca. We also found that leptin increased its own mRNA and protein expression in both cell lines, and this autocrine effect was abolished by 100-250 nM Allo-aca.ConclusionsOur data provide new insights into the role of leptin in ocular endothelial cells and represent the first original report on targeting ObR in ophthalmic cell models.

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“…Proposed mechanisms include: increased estrogen production and decreased estrogen receptor degradation, upregulated expression of VEGF and VEGFR (Dutta et al, 2012), stimulation of cyclin D1 expression, and induction of cancer stem cell survival and pluripotency (Zheng et al, 2013, 2012) in breast cancer and colorectal cancer (Bartucci et al, 2010), and increased expression of leptin receptor leading to higher levels of the anti-apoptotic protein XIAP (Cheng et al, 2010) in thyroid cancer. Leptin receptor antagonists are being developed and could be useful tools for cancer therapeutics (Otvos and Surmacz, 2011). …”

Section: Cancer and Stem Cell Biologymentioning

confidence: 99%

Comparative endocrinology of leptin: Assessing function in a phylogenetic context

Londraville

Macotela

Duff

et al. 2014

General and Comparative Endocrinology

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As we approach the end of two decades of leptin research, the comparative biology of leptin is just beginning. We now have several leptin orthologs described from nearly every major clade among vertebrates, and are moving beyond gene descriptions to functional studies. Even at this early stage, it is clear that non-mammals display clear functional similarities and differences with their better-studied mammalian counterparts. This review assesses what we know about leptin function in mammals and non-mammals, and gives examples of how these data can inform leptin biology in humans.

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Targeting the leptin receptor: a potential new mode of treatment for breast cancer

Cited by 34 publications

References 28 publications

cAMP Elevation Down-Regulates β3 Integrin and Focal Adhesion Kinase and Inhibits Leptin-Induced Migration of MDA-MB-231 Breast Cancer Cells

cAMP Elevation Down-Regulates β3 Integrin and Focal Adhesion Kinase and Inhibits Leptin-Induced Migration of MDA-MB-231 Breast Cancer Cells

Exploring Leptin Antagonism in Ophthalmic Cell Models

Comparative endocrinology of leptin: Assessing function in a phylogenetic context

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