LKB1 is required for adiponectin-mediated modulation of AMPK–S6K axis and inhibition of migration and invasion of breast cancer cells

Abstract

Adiponectin is widely known as an adipocytokine with therapeutic potential for its markedly protective function in the pathogenesis of obesity-related disorders, metabolic syndrome, systemic insulin resistance, cardiovascular disease and more recently carcinogenesis. In the present study, we show that adiponectin inhibits adhesion, invasion and migration of breast cancer cells. Further analysis of the underlying molecular mechanisms revealed that adiponectin treatment increased AMP-activated protein kinase (AMPK) phosphorylation and activity as evident by increased phosphorylation of downstream target of AMPK, acetyl-coenzyme A carboxylase and inhibition of p70S6 kinase (S6K). Intriguingly, we discovered that adiponectin treatment increases the expression of tumor suppressor gene LKB1 in breast cancer cells. Overexpression of LKB1 in breast cancer cells further increased adiponectin-mediated phosphorylation of AMPK. Using isogenic LKB1 knockdown cell line pair, we found that LKB1 is required for adiponectin-mediated modulation of AMPK-S6K axis and more importantly, inhibition of adhesion, migration and invasion of breast cancer cells. Taken together these data present a novel mechanism involving specific upregulation of tumor suppressor gene LKB1 by which adiponectin inhibits adhesion, invasion and migration of breast cancer cells. Our findings indicate the possibility of using adiponectin analogues to inhibit invasion and migration of breast cancer cells.

Transcriptome profiling in response to adiponectin in human cancer-derived cells

“…Briefly, HepG2 cells were maintained for 2 h in serum-free media with or without inhibitor; activators were then added for 3 h before cell lysis. LKB1/AMPK pathway by adiponectin leads to reduced cell proliferation, migration, and invasion, by decreasing MYC and cyclin D1 action (14,56). It has been demonstrated that MYC regulates the transcription of several ribosomal proteins (6,10,37), and a number of these were found to be downregulated by adiponectin in our work.…”

“…They have distinct tissue specificities with, for example, a predominant expression of AdipoR1 in skeletal muscle and of AdipoR2 in liver (13,32). In most cancer cells both receptors appear to be expressed, and several signaling pathways have been proposed as possible mediators of adiponectin biological effects in cancer cells (3,14,16,19,23,35,40,56,60,61). The intracellular targets of these signaling cascades are mostly unknown, with the exception of a handful of key enzymes related to lipid metabolism, such as acetyl-CoA carboxylase, which is inactivated by adiponectin through serine phosphorylation mediated by 5=-adenosine monophosphate-activated protein kinase (AMPK) (57,64).…”

Evolving role of adiponectin in cancer-controversies and update

“…Metastasis is a complex and critical aspect of cancer from a clinical perspective, with it having been estimated to be the cause of around 90% of deaths from cancer 153 . However, despite its importance little is known about this process.…”

Adenosine Monophosphate–Activated Kinase and Its Key Role in Catabolism: Structure, Regulation, Biological Activity, and Pharmacological Activation

“…Hence, reducing integrin b1 levels would lead to reduced cell migration and invasion. In addition to regulating cell polarity, studies have shown that suppression of metastasis by AMPK occurs through its ability to inhibit S6K (Taliaferro-Smith et al, 2009). Activation of AMPK resulted in the inhibition of the mTORC1 pathway (Gwinn et al, 2008), resulting in suppressed expression of proteins required for tumor growth and metastasis, including HIF-1a, MYC, and cyclin D1 (Guertin and Sabatini, 2007).…”