Different molecular signaling sustaining adiponectin action in breast cancer

Panno, Maria Luisa; Naimo, Giuseppina Daniela; Spina, Elena; Andò, Sebastiano; Mauro, Loredana

doi:10.1016/j.coph.2016.08.001

Cited by 36 publications

(48 citation statements)

References 53 publications

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“…Adiponectin concentration is inversely correlated with body mass index. Indeed, unlike most of the other adipokines, plasma adiponectin levels are found to be lower in obese individuals than in lean individuals (8,(10)(11)(12).…”

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confidence: 95%

Uncoupling effects of estrogen receptor α on LKB1/AMPK interaction upon adiponectin exposure in breast cancer

et al. 2018

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Adipose tissue is a metabolic and endocrine organ that secretes bioactive molecules called adipocytokines. Among these, adiponectin has a crucial role in obesity-associated breast cancer. The key molecule of adiponectin signaling is AMPK, which is mainly activated by liver kinase B1 (LKB1). Here, we demonstrated that estrogen receptor-α (ERα)/LKB1 interaction may negatively interfere with the LKB1 capability to phosphorylate AMPK and inhibit its downstream signaling TSC2/mTOR/p70S6k. In adiponectin-treated MCF-7 cells, AMPK signaling was not working, resulting in its downstream target acetyl-CoA carboxylase (ACC) being still active. In contrast, in MDA-MB-231 cells, AMPK and ACC phosphorylation was enhanced by adiponectin, inhibiting lipogenesis and cell growth. Upon adiponectin, ERα signaling switched the energy balance of breast cancer cells toward a lipogenic phenotype. Therefore, adiponectin played an inhibitory role on ERα-negative cell growth and progression in vitro and in vivo. In contrast, low adiponectin levels, similar to those circulating in obese patients, acted on ERα-positive cells as a growth factor, stimulating proliferation. The latter effect was blunted in vivo by high adiponectin concentration. All this may have translational relevance, addressing how the handling of adiponectin, as a therapeutic tool in breast cancer treatment, needs to be carefully considered in ERα-positive obese patients, where circulating levels of this adipocytokine are relatively low. In other words, in ERα-positive breast cancer obese patients, higher adiponectin doses should be administered with respect to ERα-negative breast cancer, also opportunely combined with antiestrogen therapy. -Mauro, L., Naimo, G. D., Gelsomino, L., Malivindi, R., Bruno, L., Pellegrino, M., Tarallo, R., Memoli, D., Weisz, A., Panno, M. L., Andò, S. Uncoupling effects of estrogen receptor α on LKB1/AMPK interaction upon adiponectin exposure in breast cancer.

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Uncoupling effects of estrogen receptor α on LKB1/AMPK interaction upon adiponectin exposure in breast cancer

et al. 2018

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“…The proliferative effect in osteoblasts is mediated via AdipoR1 and requires the activation of p38 mitogen-activated protein kinase (MAPK) and c-jun N-terminal kinase (JNK) [27,54]. Activation of p38-MAPK and JNK by adiponectin has been determined in numerous other cell types and tissues, although the effect of these signaling molecules on cell proliferation depends on cellular context [55]. Suppression of AdipoR1 with small-interfering RNA (siRNA) abolished the activation of these signaling pathways and the stimulation of osteoblast proliferation [27,54].…”

Section: The Effect Of Adiponectin On Proliferation and Induction Ofmentioning

confidence: 99%

The Activity of Adiponectin in Bone

2016

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The adipokine adiponectin affects multiple target tissues and plays important roles in glucose metabolism and whole-body energy homeostasis. Circulating adiponectin levels in obese people are lower than in non-obese, and increased serum adiponectin is associated with weight loss. Numerous clinical studies have established that fat mass is positively related to bone mass, a relationship that is maintained by communication between the two tissues through hormones and cytokines. Since adiponectin levels inversely correspond to fat mass, its bone effects and its potential contribution to the relationship between fat and bone have been investigated. In clinical observational studies, adiponectin was found to be negatively associated with bone mineral density, suggesting it might be a negative regulator of bone metabolism. In order to identify the mechanisms that underlie the activity of adiponectin in bone, a large number of laboratory studies in vitro and in animal models of mice over-expressing or deficient of adiponectin have been carried out. Results of these studies are not entirely congruent, partly due to variation among experimental systems and partly due to the complex nature of adiponectin signaling, which involves a combination of multiple direct and indirect mechanisms.

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“…Both AdipoR1 and AdipoR2 are seven‐transmembrane proteins, structurally, functionally and topologically similar to G protein‐coupled receptors, but with opposite orientation of N‐terminus, found to be cytoplasmic, and C‐terminus, that is extracellular . The activation of AdipoR1 and AdipoR2 induces the formation of homodimeric and heterodimeric complexes, affecting the main adiponectin target, AMP‐activated protein kinase (AMPK), which controls cellular metabolic rate . The existence of these distinct adiponectin receptors can be related to the different affinities of adiponectin isoforms, which display wide biological actions in different tissues.…”

Section: Adiponectin and Breast Cancermentioning

confidence: 99%

“…The screening of several molecules belonging to natural products, prevalently used in traditional Chinese medicine, allowed the identification of AdipoR1 agonists, such as matairesinol and arcitiin, or AdipoR2 agonists, including partenolide and toxifolid. These compounds may be useful due to their anti‐proliferative, anti‐inflammatory, pro‐apoptotic and anti‐cancer properties . Moreover, it cannot be disregarded that healthy lifestyle, characterized by equilibrate dietary and physical activity, may influence adiponectin levels and overall may represent a useful strategy for obesity‐related breast cancer prevention …”

Section: Adiponectin As a Potential Therapeutic Toolmentioning

confidence: 99%

“…These compounds may be useful due to their anti‐proliferative, anti‐inflammatory, pro‐apoptotic and anti‐cancer properties . Moreover, it cannot be disregarded that healthy lifestyle, characterized by equilibrate dietary and physical activity, may influence adiponectin levels and overall may represent a useful strategy for obesity‐related breast cancer prevention …”

Section: Adiponectin As a Potential Therapeutic Toolmentioning

confidence: 99%

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Novel insights into adiponectin action in breast cancer: Evidence of its mechanistic effects mediated by ERα expression

et al. 2020

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Summary This review describes the multifaceted effects of adiponectin on breast cancer cell signalling, tumour metabolism, and microenvironment. It is largely documented that low adiponectin levels are associated with an increased risk of breast cancer. However, it needs to be still clarified what are the extents of the decrease of local/intra‐tumoural adiponectin concentrations, which promote breast tumour malignancy. Most of the anti‐proliferative and pro‐apoptotic effects induced by adiponectin have been obtained in breast cancer cells not expressing estrogen receptor alpha (ERα). Here, we will highlight recent findings demonstrating the mechanistic effects through which adiponectin is able to fuel genomic and non‐genomic estrogen signalling, inhibiting LKB1/AMPK/mTOR/S6K pathway and switching energy balance. Therefore, it emerges that the reduced adiponectin levels in patients with obesity work to sustain tumour growth and progression in ERα‐positive breast cancer cells. All this may contribute to remove the misleading paradigm that adiponectin univocally inhibits breast cancer cell growth and progression independently on ERα status. The latter concept, here clearly provided by pre‐clinical studies, may have translational relevance adopting adiponectin as a potential therapeutic tool. Indeed, the interfering role of ERα on adiponectin action addresses how a separate assessment of adiponectin treatment needs to be considered in novel therapeutic strategies for ERα‐positive and ERα‐negative breast cancer.

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Different molecular signaling sustaining adiponectin action in breast cancer

Cited by 36 publications

References 53 publications

Uncoupling effects of estrogen receptor α on LKB1/AMPK interaction upon adiponectin exposure in breast cancer

Uncoupling effects of estrogen receptor α on LKB1/AMPK interaction upon adiponectin exposure in breast cancer

The Activity of Adiponectin in Bone

Novel insights into adiponectin action in breast cancer: Evidence of its mechanistic effects mediated by ERα expression

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