PKA/AMPK signaling in relation to adiponectin’s antiproliferative effect on multiple myeloma cells

Abstract

Obesity increases the risk of developing multiple myeloma (MM). Adiponectin is a cytokine produced by adipocytes, but paradoxically decreased in obesity, that has been implicated in MM progression. Herein, we evaluated how prolonged exposure to adiponectin affected the survival of MM cells as well as putative signaling mechanisms. Adiponectin activates protein kinase A (PKA), which leads to decreased AKT activity and increased AMP-activated protein kinase (AMPK) activation. AMPK, in turn, induces cell cycle arrest and apoptosis. Adiponectin-induced apoptosis may be mediated, at least in part, by the PKA/AMPK-dependent decline in the expression of the enzyme acetyl-CoA-carboxylase (ACC), which is essential to lipogenesis. Supplementation with palmitic acid, the preliminary end product of fatty acid synthesis, rescues MM cells from adiponectin-induced apoptosis. Furthermore, 5-(tetradecyloxy)-2-furancarboxylic acid (TOFA), an ACC inhibitor, exhibited potent antiproliferative effects on MM cells that could also be inhibited by fatty acid supplementation. Thus, adiponectin's ability to reduce survival of MM cells appears to be mediated through its ability to suppress lipogenesis. Our findings suggest that PKA/AMPK pathway activators, or inhibitors of ACC, may be useful adjuvants to treat MM. Moreover, the antimyeloma effect of adiponectin supports the concept that hypoadiponectinemia, as occurs in obesity, promotes MM tumor progression.

Adipocytes secreted leptin is a pro-tumor factor for survival of multiple myeloma under chemotherapy

“…Previous studies showed an inverse correlation between plasma concentration of adiponectin and incidence of breast, prostate, colorectal, and acute myeloid leukemia [9, 10, 13, 19]. Adiponectin is suggested to be a protective factor by exerting anti-inflammation, insulin-sensitizing, and anti-angiogenesis [20–22]. …”

Bone Marrow Adipocytes Facilitate Fatty Acid Oxidation Activating AMPK and a Transcriptional Network Supporting Survival of Acute Monocytic Leukemia Cells

“…BM-adipocytes, the major source of serum adiponectin that increases during caloric restriction as well as during cancer therapy (37), has been shown to contribute to chemotherapy resistance via adipocyte-secreted adipokines and AMPK-dependent autophagy activation in myeloma cells (38). Our co-culture experiments conducted in serum-starved conditions also demonstrated adiponectin production by BM-adipocytes.…”

Adiponectin as a biomarker linking obesity and adiposopathy to hematologic malignancies

“…Myeloma cell apoptosis is decreased in myeloma-bearing adiponectin-deficient mice while increasing adiponectin via an apolipoprotein peptide mimetic L-4F increased myeloma cells apoptosis in vitro and in vivo, reduced myeloma tumor burden and prevented myeloma bone disease [82,107]. A very recent experimental study has shown that adiponectin's ability to enhance MM cell cycle arrest and apoptosis was attributed to the suppression of lipogenesis through the protein kinase A (PKA)/ AMPK-dependent decline of the enzyme expression acetyl-CoA-carboxylase (ACC), suggesting that ACC inhibitors or PKA/AMPK pathway activators could be used as therapeutic adjuvants in MM [108]. …”