Targeting AMP-activated protein kinase in adipocytes to modulate obesity-related adipokine production associated with insulin resistance and breast cancer cell proliferation

Abstract

BackgroundAdipokines, e.g. TNFα, IL-6 and leptin increase insulin resistance, and consequent hyperinsulinaemia influences breast cancer progression. Beside its mitogenic effects, insulin may influence adipokine production from adipocyte stromal cells and paracrine enhancement of breast cancer cell growth. In contrast, adiponectin, another adipokine is protective against breast cancer cell proliferation and insulin resistance.AMP-activated protein kinase (AMPK) activity has been found decreased in visceral adipose tissue of insulin-resistant patients. Lipopolysaccharides (LPS) link systemic inflammation to high fat diet-induced insulin resistance. Modulation of LPS-induced adipokine production by metformin and AMPK activation might represent an alternative way to treat both, insulin resistance and breast cancer.MethodsHuman preadipocytes obtained from surgical biopsies were expanded and differentiated in vitro into adipocytes, and incubated with siRNA targeting AMPKalpha1 (72 h), LPS (24 h, 100 μg/ml) and/or metformin (24 h, 1 mM) followed by mRNA extraction and analyses. Additionally, the supernatant of preadipocytes or derived-adipocytes in culture for 24 h was used as conditioned media to evaluate MCF-7 breast cancer cell proliferation.ResultsConditioned media from preadipocyte-derived adipocytes, but not from undifferentiated preadipocytes, increased MCF-7 cell proliferation (p < 0.01). Induction of IL-6 mRNA by LPS was reduced by metformin (p < 0.01), while the LPS-induced mRNA expression of the naturally occurring anti-inflammatory cytokine interleukin 1 receptor antagonist was increased (p < 0.01). Silencing of AMPKalpha1 enhanced LPS-induced IL-6 and IL-8 mRNA expression (p < 0.05).ConclusionsAdipocyte-secreted factors enhance breast cancer cell proliferation, while AMPK and metformin improve the LPS-induced adipokine imbalance. Possibly, AMPK activation may provide a new way not only to improve the obesity-related adipokine profile and insulin resistance, but also to prevent obesity-related breast cancer development and progression.

AMP-activated protein kinase signaling is upregulated in papillary thyroid cancer

“…Further evidence for AMPK anti-proliferative effects on tumor cells relies on the fact that the major kinase that phosphorylates and activates AMPK has been identified to be the tumor suppressor kinase LKB1 (9). The previous findings showing that the oral anti-diabetic drug, metformin, inhibits proliferation of epithelial cells derived from breast, prostate, and ovarian cancers, effects that require both LKB1 and AMPK, are consistent with the concept that AMPK pathway might be implicated in tumor cell biology (1,11,12,13). Also, several epidemiological studies demonstrated that the chronic use of metformin is associated with a lower incidence of cancer (1,13).…”

Leptin promotes the proliferation and migration of human breast cancer through the extracellular-signal regulated kinase pathway

“…Furthermore, the conditioned media from preadipocyte-derived adipocytes, but not that from undifferentiated preadipocytes, increased MCF-7 cell proliferation (35). Dietary fat increases mammary tumor growth and metastasis, thereby increasing the risk of mortality in obesity-resistant mice (36).…”

Pre-treatment with metformin activates Nrf2 antioxidant pathways and inhibits inflammatory responses through induction of AMPK after transient global cerebral ischemia

“…The potential role of metformin in suppressing inflammation has been reported in various cell types such as pancreatic cells (Yue et al 2014), hepatocytes (Woudenberg-Vrenken et al 2013), neurons (Russe et al 2013) as well adipocytes (Grisouard et al 2011). Moreover, studies have established that activation of AMPK by other inducers; can attenuate cytokines against ischemic injuries in different organs (Jing et al 2013;Miller et al 2008).…”