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Fatty Acid Oxidation Mediated by Acyl-CoA Synthetase Long Chain 3 Is Required for Mutant KRAS Lung Tumorigenesis

Mahesh S Padanad1, Georgia Konstantinidou1, Niranjan Venkateswaran1

  • 1Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Cell Reports
|August 2, 2016
PubMed

Insights

Mutant KRAS drives lung cancer by reprogramming fatty acid metabolism via ACSL3. Inhibiting ACSL3 depletes ATP, causing cell death and halting tumor growth, offering a potential therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Metabolic Research

Background:

  • KRAS is a frequently mutated oncogene in human cancers.
  • Mutant KRAS alters cellular metabolism, but its role in tumorigenesis is not fully understood.
  • Understanding metabolic reprogramming in KRAS-mutant cancers is crucial for developing targeted therapies.

Purpose of the Study:

  • To investigate the role of cellular metabolism, specifically fatty acid metabolism, in mutant KRAS-driven lung cancer.
  • To identify key metabolic regulators involved in mutant KRAS tumorigenesis.
  • To explore potential therapeutic targets based on metabolic vulnerabilities.

Main Methods:

  • Investigated the role of Acyl-coenzyme A (CoA) synthetase long-chain family member 3 (ACSL3) in mutant KRAS lung cancer cells.
  • Assessed the impact of ACSL3 suppression on cellular ATP levels and cell viability.
  • Examined the effects of mutant KRAS on fatty acid uptake, retention, accumulation, and beta-oxidation.
  • Evaluated the in vivo tumorigenesis of mutant KRAS lung cancer with ACSL3 suppression.
  • Analyzed ACSL3 expression in human lung cancer tissues.

Main Results:

  • Mutant KRAS regulates intracellular fatty acid metabolism through ACSL3.
  • ACSL3 suppression leads to ATP depletion and cell death in lung cancer cells.
  • Mutant KRAS enhances fatty acid uptake, accumulation, and beta-oxidation in an ACSL3-dependent manner.
  • ACSL3 is essential for mutant KRAS lung cancer tumorigenesis in vivo.
  • ACSL3 is highly expressed in human lung cancer.

Conclusions:

  • Mutant KRAS reprograms lipid homeostasis in lung cancer.
  • ACSL3 is a critical mediator of mutant KRAS-driven metabolic adaptation.
  • Targeting ACSL3 represents a potential therapeutic strategy for mutant KRAS lung cancers.
Keywords:
ACSL3cancer metabolismfatty acid oxidationlipid metabolismlung cancermouse cancer modelsmutant KRAS

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