Abstract
BackgroundTargeting cell metabolism offers promising opportunities for the development of drugs to treat cancer. We previously found that the fatty acyl-CoA synthetase VL3 (ACSVL3) is elevated in malignant brain tumor tissues and involved in tumorigenesis. This study investigates the role of ACSVL3 in the maintenance of glioblastoma multiforme (GBM) stem cell self-renewal and the capacity of GBM stem cells to initiate tumor xenograft formation.MethodsWe examined ACSVL3 expression during differentiation of several GBM stem cell enriched neurosphere cultures. To study the function of ACSVL3, we performed loss-of-function by using small interfering RNAs to target ACSVL3 and examined stem cell marker expression, neurosphere formation and tumor initiation properties.ResultsACSVL3 expression levels were substantially increased in GBM stem cell enriched neurosphere cultures and decreased after differentiation of the neurospheres. Down-regulating ACSVL3 with small inhibiting RNAs decreased the expression of markers and regulators associated with stem cell self-renewal, including CD133, ALDH, Musashi-1 and Sox-2. ACSVL3 knockdown in neurosphere cells led to increased expression of differentiation markers GFAP and Tuj1. Furthermore, ACSVL3 knockdown reduced anchorage-independent neurosphere cell growth, neurosphere-forming capacity as well as self-renewal of these GBM stem cell enriched neurosphere cultures. In vivo studies revealed that ACSVL3 loss-of-function substantially inhibited the ability of neurosphere cells to propagate orthotopic tumor xenografts. A link between ACSVL3 and cancer stem cell phenotype was further established by the findings that ACSVL3 expression was regulated by receptor tyrosine kinase pathways that support GBM stem cell self-renewal and tumor initiation, including EGFR and HGF/c-Met pathways.ConclusionsOur findings indicate that the lipid metabolism enzyme ACSVL3 is involved in GBM stem cell maintenance and the tumor-initiating capacity of GBM stem cell enriched-neurospheres in animals.
Highlights
Targeting cell metabolism offers promising opportunities for the development of drugs to treat cancer
Our findings indicate that the lipid metabolism enzyme acyl-coenzyme A (CoA) synthetase VL3 (ACSVL3) is involved in glioblastoma multiforme (GBM) stem cell maintenance and the tumor-initiating capacity of GBM stem cell enriched-neurospheres in animals
ACSVL3 expression correlates inversely with differentiation of GBM stem cells Human GBM neurosphere cultures that are enriched with cancer stem cells, including HSR-GBM1A, HSR-GBM1B, GBM-DM14602 and primary GBM neurosphere isolates from GBM patients, have been extensively characterized by us and others in terms of their stem cell marker expression, differentiation potential and tumor initiation capacity [16,21,24,25,29,30]
Summary
Targeting cell metabolism offers promising opportunities for the development of drugs to treat cancer. We previously found that the fatty acyl-CoA synthetase VL3 (ACSVL3) is elevated in malignant brain tumor tissues and involved in tumorigenesis. Targeting cancer specific metabolism represents an opportunity to develop novel, potentially selective and broadly applicable drugs to treat a multiplicity of cancer types. In the lipid metabolism cascade, addition of coenzyme A (CoA) to fatty acids is a fundamental initial step in the utilization of fatty acids for structural and storage lipid biosynthesis, signaling lipid protein acylation, and other metabolic processes [8]. Acyl-CoA synthetases (ACSs) are key enzymes for this fatty acid activation step [9]. ACS catalyzes an ATP-dependent multi-substrate reaction, resulting in the formation of fatty acyl-CoA. The overall reaction scheme is: Fatty acid þ ATP þ CoA→Fatty acyl−CoA þ PPi þ AMP
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