Inhibition of StearoylCoA Desaturase-1 Inactivates Acetyl-CoA Carboxylase and Impairs Proliferation in Cancer Cells: Role of AMPK

Abstract

Cancer cells activate the biosynthesis of saturated fatty acids (SFA) and monounsaturated fatty acids (MUFA) in order to sustain an increasing demand for phospholipids with appropriate acyl composition during cell replication. We have previously shown that a stable knockdown of stearoyl-CoA desaturase 1 (SCD1), the main Δ9-desaturase that converts SFA into MUFA, in cancer cells decreases the rate of lipogenesis, reduces proliferation and in vitro invasiveness, and dramatically impairs tumor formation and growth. Here we report that pharmacological inhibition of SCD1 with a novel small molecule in cancer cells promoted the activation of AMP-activated kinase (AMPK) and the subsequent reduction of acetylCoA carboxylase activity, with a concomitant inhibition of glucose-mediated lipogenesis. The pharmacological inhibition of AMPK further decreased proliferation of SCD1-depleted cells, whereas AMPK activation restored proliferation to control levels. Addition of supraphysiological concentrations of glucose or pyruvate, the end product of glycolysis, did not reverse the low proliferation rate of SCD1-ablated cancer cells. Our data suggest that cancer cells require active SCD1 to control the rate of glucose-mediated lipogenesis, and that when SCD1 activity is impaired cells downregulate SFA synthesis via AMPK-mediated inactivation of acetyl-CoA carboxylase, thus preventing the harmful effects of SFA accumulation.

Metformin and Pancreatic Cancer Metabolism

“…Interestingly, there was an inhibition in cellular proliferation and anchorage-independent growth in the SCD knockdown cells [114]. Other studies confirm that SCD inhibition by chemical or genetic manipulations resulted in inhibition of cancer cell proliferation and/or death [115][116][117][118]. Thus, SCD appears to be involved in modulating lipid metabolism and signaling processes crucial for cancer cell replication and anchorage-independent growth, effects are likely influenced by the effects of SCD loss on membrane integrity [114].…”

Lipogenesis in cancer progression (Review)

“…Elevated ACC expression is observed in the early stage of breast cancer (14) and silencing its expression results in growth inhibition and apoptosis of cancer cells (15)(16)(17). High SCD1 expression is associated with cancer cell proliferation (18) and with a decrease in cell death (18)(19)(20)(21). SREBP1c also plays a role in the transformation of normal cells (22).…”

“…In these conditions, expressions of key proteins involved in cell cycle progression are decreased. The degree of SCD1 inhibition appears directly correlated with inhibition of cancer cells proliferation (19) decreasing the amount of SFA (SCD1 substrates), the main inhibitors of ACC (82).…”

“…Androgen activates the cleavage of SREBP by increasing the (19) AKT/GSK3β (20) expression of SCAP and INSIG (57). SREBP1 also increases reactive oxygen species (ROS) production (101) inducing tumor progression (102).…”

Molecular mechanisms for survival regulation of chronic myeloid leukemia stem cells

“…On the other hand, given the specifi c roles of Blk and Scd1 in CML LSCs (Zhang et al, 2012a(Zhang et al, , 2012c, restoration of Blk expression or enhancement of Scd1 activity provides an effective strategy for specifi cally targeting LSCs in CML. and tumorigenesis (Kim and Ntambi, 1999;Falvella et al, 2002;Scaglia and Igal, 2005;Scaglia et al, 2009;Hess et al, 2010). Deletion of Scd1 leads to decreased synthesis of lipids, especially triglycerides, and causes the resistance to leptin-defi cient-induced and diet-induced obesity via increased insulin sensitivity (Flowers et al, 2007).…”