Stearoyl CoA Desaturase-1 Silencing in Glioblastoma Cells: Phospholipid Remodeling and Cytotoxicity Enhanced upon Autophagy Inhibition

Abstract

Modulation of lipid metabolism is a well-established cancer hallmark, and SCD1 has been recognized as a key enzyme in promoting cancer cell growth, including in glioblastoma (GBM), the deadliest brain tumor and a paradigm of cancer resistance. The central goal of this work was to identify, by MS, the phospholipidome alterations resulting from the silencing of SCD1 in human GBM cells, in order to implement an innovative therapy to fight GBM cell resistance. With this purpose, RNAi technology was employed, and low serum-containing medium was used to mimic nutrient deficiency conditions, at which SCD1 is overexpressed. Besides the expected increase in the saturated to unsaturated fatty acid ratio in SCD1 silenced-GBM cells, a striking increase in polyunsaturated chains, particularly in phosphatidylethanolamine and cardiolipin species, was noticed and tentatively correlated with an increase in autophagy (evidenced by the increase in LC3BII/I ratio). The contribution of autophagy to mitigate the impact of SCD1 silencing on GBM cell viability and growth, whose modest inhibition could be correlated with the maintenance of energetically associated mitochondria, was evidenced by using autophagy inhibitors. In conclusion, SCD1 silencing could constitute an important tool to halt GBM resistance to the available treatments, especially when coupled with a mitochondria disrupter chemotherapeutic.

Machine Learning-Based Integrated Multiomics Characterization of Colorectal Cancer Reveals Distinctive Metabolic Signatures

“…LPCAT1-derived saturated PC (e.g., PC (30:0)) is essential for tumor growth . The saturation of phospholipids also contributes significantly to cell proliferation . Some works reported that controlling the membrane structure and signaling activity by regulating PC saturation determined the invasive behavior of cancer cells. ,, The plasmalogen lipids (e.g., PC O-34:3) regulate many aspects of cell membrane homeostasis, including signal transduction, cell proliferation, and reduction of oxidative stress. , The plasmalogen lipids are potential prognostic biomarkers for CRC metastasis .…”

Emerging Lipid Targets in Glioblastoma

“…SCD-1 knockdown was shown to re-sensitize cells to TMZ treatment, while a combined therapy of TMZ and SCD-1 inhibitor was found to reduce the mobility and viability of GBM cells [98]. A study of the phospholipidome proposed that silencing SCD-1 might help to overcome GBM treatment resistance in combined therapies [99]. Moreover, several intracranial tumors including GBM were shown to display high or increased activity of the LDL receptor, a receptor responsible for cholesterol transportation, making these cells highly dependent on cholesterol supply [100].…”

Toward a Unifying Hypothesis for Redesigned Lipid Catabolism as a Clinical Target in Advanced, Treatment-Resistant Carcinomas

“…Zhang et al showed that SCD1 was essential to stem cell-like behavior and chemoresistance in gastric carcinoma [ 165 ]. Morais et al [ 166 ] and Parik et al [ 167 ] showed that glioblastoma aggressiveness and temozolomide resistance depended on SCD1 expression. Lien et al showed that in vivo PDAC growth under low lipid dietary availability was strongly dependent on SCD1 [ 168 ].…”