1. Academic Validation
  2. Fatty acid synthase (FASN) regulates the mitochondrial priming of cancer cells

Fatty acid synthase (FASN) regulates the mitochondrial priming of cancer cells

  • Cell Death Dis. 2021 Oct 21;12(11):977. doi: 10.1038/s41419-021-04262-x.
Barbara Schroeder  # 1 2 3 Travis Vander Steen  # 1 Ingrid Espinoza  # 4 5 Chandra M Kurapaty Venkatapoorna 1 6 Zeng Hu 1 7 Fernando Martín Silva 8 Kevin Regan 9 Elisabet Cuyàs 10 11 X Wei Meng 12 Sara Verdura 10 11 Aina Arbusà 10 11 Paula A Schneider 12 Karen S Flatten 12 George Kemble 13 Joan Montero 8 Scott H Kaufmann 2 12 Javier A Menendez 14 15 Ruth Lupu 16 17 18
Affiliations

Affiliations

  • 1 Division of Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA.
  • 2 Mayo Clinic Cancer Center, Rochester, MN, 55905, USA.
  • 3 Helmholtz Pioneer Campus, Heimholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Ingolstädter Landstraße 1 D-85764 Neuherberg, Munich, Germany.
  • 4 Department of Preventive Medicine, John D. Bower School of Population Health, University of Mississippi Medical Center, Jackson, MS, 39216, USA.
  • 5 Cancer Institute, School of Medicine, University of Mississippi Medical Center, Jackson, MS, 39216, USA.
  • 6 Department of Nutrition, Dietetics, and Hospital Management, Auburn University, Auburn, AL, 36849, USA.
  • 7 Radiation Oncology Research, Mayo Clinic, Rochester, MN, 55905, USA.
  • 8 Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology (BIST), 08028, Barcelona, Spain.
  • 9 Department of Experimental Pathology, Mayo Clinic, Rochester, MN, 55905, USA.
  • 10 Girona Biomedical Research Institute, 17190, Salt, Girona, Spain.
  • 11 Program Against Cancer Therapeutic Resistance (ProCURE), Metabolism & Cancer Group, Catalan Institute of Oncology, 17007, Girona, Spain.
  • 12 Deparment of Oncology, Mayo Clinic, Rochester, MN, 55905, USA.
  • 13 Sagimet Biosciences (formerly 3-V Biosciences), San Mateo, CA, 94402, USA.
  • 14 Department of Experimental Pathology, Mayo Clinic, Rochester, MN, 55905, USA. jmenendez@idibgi.org.
  • 15 Girona Biomedical Research Institute, 17190, Salt, Girona, Spain. jmenendez@idibgi.org.
  • 16 Division of Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA. lupu.ruth@mayo.edu.
  • 17 Mayo Clinic Cancer Center, Rochester, MN, 55905, USA. lupu.ruth@mayo.edu.
  • 18 Department of Biochemistry and Molecular Biology Laboratory, Mayo Clinic Laboratory, Rochester, MN, 55905, USA. lupu.ruth@mayo.edu.
  • # Contributed equally.
Abstract

Inhibitors of the lipogenic Enzyme fatty acid synthase (FASN) have attracted much attention in the last decade as potential targeted Cancer therapies. However, little is known about the molecular determinants of Cancer cell sensitivity to FASN inhibitors (FASNis), which is a major roadblock to their therapeutic application. Here, we find that pharmacological starvation of endogenously produced FAs is a previously unrecognized metabolic stress that heightens mitochondrial apoptotic priming and favors cell death induction by BH3 mimetic inhibitors. Evaluation of the death decision circuits controlled by the Bcl-2 Family of proteins revealed that FASN inhibition is accompanied by the upregulation of the pro-death BH3-only proteins Bim, PUMA, and NOXA. Cell death triggered by FASN inhibition, which causally involves a palmitate/NADPH-related redox imbalance, is markedly diminished by concurrent loss of Bim or PUMA, suggesting that FASN activity controls Cancer cell survival by fine-tuning the BH3 only proteins-dependent mitochondrial threshold for Apoptosis. FASN inhibition results in a heightened mitochondrial Apoptosis priming, shifting cells toward a primed-for-death state "addicted" to the anti-apoptotic protein Bcl-2. Accordingly, co-administration of a FASNi synergistically augments the apoptosis-inducing activity of the dual BCL-XL/Bcl-2 Inhibitor ABT-263 (navitoclax) and the Bcl-2 specific BH3-mimetic ABT-199 (venetoclax). FASN inhibition, however, fails to sensitize breast Cancer cells to MCL-1- and BCL-XL-selective inhibitors such as S63845 and A1331852. A human breast Cancer xenograft model evidenced that oral administration of the only clinically available FASNi drastically sensitizes FASN-addicted breast tumors to ineffective single-agents navitoclax and venetoclax in vivo. In summary, a novel FASN-driven facet of the mitochondrial priming mechanistically links the redox-buffering mechanism of FASN activity to the intrinsic apoptotic threshold in breast Cancer cells. Combining next-generation FASNis with BCL-2-specific BH3 mimetics that directly activate the apoptotic machinery might generate more potent and longer-lasting antitumor responses in a clinical setting.

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