ω3-polyunsaturated fatty acids induce cell death through apoptosis and autophagy in glioblastoma cells: In vitro and in vivo

Abstract

Among brain tumors, glioblastoma (GBM) is the most aggressive type and is associated with the lowest patient survival rate. Numerous lines of evidence have established that omega-3-polyunsaturated fatty acids (ω3-PUFAs) have potential for the prevention and therapy of several types of cancers. Docosahexaenoic acid (DHA), an ω3-PUFA, was reported to inhibit growth and induce apoptotic and autophagic cell death in several cancer cell lines; however, its effects on GBM cells are still unknown. in the present study, we examined the cytotoxic effect of DHA on the GBM cell lines, D54MG, U87MG, U251MG and GL261. Treatment of GBM cells with DHA induced PARP cleavage, increased the population of sub-G1 cells, and increased the number of TUNEL-positive cells, which are all indicative of apoptosis. Furthermore, treatment of GBM cells with DHA resulted in a significant increase in autophagic activity, as revealed by increased LC3-II levels, GFP-LC3 puncta, and autophagic flux activation, accompanied by activation of 5'-AMP-activated protein kinase (AMPK) and decreases in phosphorylated Akt (p-AktSer473) levels and mTOR activity. In vivo, endogenous expression of Caenorhabditis elegans ω3-desaturase, which converts ω6-PUFAs to ω3-PUFAs, in fat-1 transgenic mice yielded a significant decrease in tumor volume following subcutaneous injection of mouse glioma cells (GL261), when compared with wild-type mice. TUNEL-positive cell numbers and LC3-II levels were elevated in tumor tissue from the fat-1 transgenic mice compared with tumor tissue from the wild-type mice. In addition, p-Akt levels were decreased and p-AMPK levels were increased in tumor tissue from the fat-1 transgenic mice. These results indicate that ω3-PUFAs induce cell death through apoptosis and autophagy in GBM cells; thus, it may be possible to use ω3-PUFAs as chemopreventive and therapeutic agents for GBM.

Omega-3 Docosahexaenoic Acid (DHA) Impedes Silica-Induced Macrophage Corpse Accumulation by Attenuating Cell Death and Potentiating Efferocytosis

“…The effect of ω-3 PUFAs on apoptosis appears to be cell type and context dependent. It has been demonstrated in multiple types of cancer that ω-3 PUFAs can induce apoptotic cell death at concentrations similar to those employed in this manuscript ( 55 – 57 ). However, studies in other cell types including cardiomyocytes, neurons, monocyte-like cells, and primary monocytes show that ω-3 PUFAs in fact confer protection against apoptotic stimuli ( 58 – 60 ).…”

Determining the Cytotoxicity of Oxidized Lipids in Cultured Caco-2 Cells Using Bioimaging Techniques

“…In addition, apoptosis is associated with stimulating cysteine aspartic acid-specific proteases recognised in form of caspases [7,8]. Notably, early investigations have found PUFAs to promote apoptosis and prevent cellular proliferation in vitro [9,10].…”

Opposite Regulation of CHOP and GRP78 and Synergistic Apoptosis Induction by Selenium Yeast and Fish Oil via AMPK Activation in Lung Adenocarcinoma Cells

“…In addition to invasion and metastasis inhibition, apoptosis induction also has been suggested to underlie the anticancer effects of FO omega-3 fatty acids [ 16 ]. Moreover, like selenium, their apoptosis induction effects in cancer cells are also involved with the activation of AMPK [ 16 , 18 , 21 , 22 ] and caspase-4 [ 23 ], as well as the modulation of ER stress markers, such as CHOP [ 23 ] and GRP78 [ 24 ].…”