Peroxisome proliferator-activated receptor-γ protects ERBB2-positive breast cancer cells from palmitate toxicity

Abstract

Introduction Accumulation of fatty acids and neutral lipids in nonadipose tissues is cytotoxic. We recently showed that ERBB2-positive breast cancer cells produce significantly high amounts of fats, because of overexpression of the peroxisome proliferator-activated receptor (PPAR)γ-binding protein and the nuclear receptor NR1D1 (nuclear receptor subfamily 1, group D, member 1; Rev-erbα). These genes upregulate de novo fatty acid synthesis, which is a critical pathway for the energy production and survival of these cells. NR1D1 and PPARγ-binding protein are functionally related to PPARγ, a well established positive regulator of adipogenesis and lipid storage.

Influence of 17β-Estradiol on 15-Deoxy-Δ12,14Prostaglandin J2-Induced Apoptosis in MCF-7 and MDA-MB-231 Cells

“…Our findings are in agreement with previous reports of PGJ2-induced mitochondrial dysfunction and ROS production in MCF-7 cells (Pignatelli et al, 2005;Kim et al, 2008). In order to determine whether PGJ2 apoptotic action is dependent on PPARγ activation, 10 μM of the irreversible PPARγ antagonist, GW9962, was used to completely block PPARγ active site (Seargent et al, 2004;Kourtidis et al, 2009). GW9962 is also suitable because it does not affect PPARγ-mediated transcription (Leesnitzer et al, 2002).…”

Heterogeneity of fatty acid metabolism in breast cancer cells underlies differential sensitivity to palmitate‐induced apoptosis

“…Palmitate also impairs MDA‐MB‐231 cell proliferation and activates apoptosis (Baumann et al ., 2016; Hardy et al ., 2000, 2003; Kourtidis et al ., 2009; Wu et al ., 2017) via a number of mechanisms, including ER stress (Baumann et al ., 2016; Boslem et al ., 2011), impaired autophagy (RostamiRad et al ., 2018; Wu et al ., 2017), altered NAD metabolism (Penke et al ., 2017), and ceramide synthesis (Luo et al ., 2017). Importantly, many of the deleterious effects of palmitate on cellular function are mitigated by cotreatment with other FAs, in particular the monounsaturated FA oleate (Colvin et al ., 2017; Kim et al ., 2017; Penke et al ., 2017; Sargsyan et al ., 2016), which itself is pro‐proliferative and activates phosphoinositide 3‐kinase signaling (Hardy et al ., 2000).…”

Acid ceramidase as a therapeutic target in metastatic prostate cancer

“…The reaction mixture contained 250 µl of 0.1 M phosphate buffer (pH 6.5) with 0.3 M KCl, 0.1 mM EDTA, and 3 mM DTT; 30 µl of substrate solution (L-pyroglutamyl-L-phenylalanyl-L-leucine-p -nitroanilide; 2.2 mM many neoplastic cells activate to offset the toxic accumulation of palmitate is its peroxisome proliferator-activated receptor (PPAR) ␥ -dependent funneling to eventually form triglycerides, which can be further used as energy stores ( 4 ). A second pathway followed by palmitate is the condensation of palmitoyl CoA with L-serine, leading to the synthesis of ceramides ( 5 ).…”