2. Academic Validation
  3. Ovarian cancer cell fate regulation by the dynamics between saturated and unsaturated fatty acids

Ovarian cancer cell fate regulation by the dynamics between saturated and unsaturated fatty acids

  • Proc Natl Acad Sci U S A. 2022 Oct 11;119(41):e2203480119. doi: 10.1073/pnas.2203480119.
Guangyuan Zhao 1 2,  Yuying Tan 3,  Horacio Cardenas 1,  David Vayngart 4,  Yinu Wang 1,  Hao Huang 1,  Russell Keathley 1 2,  Jian-Jun Wei 5 6,  Christina R Ferreira 7,  Sandra Orsulic 8 9,  Ji-Xin Cheng 3 10 11,  Daniela Matei 1 6 12
Affiliations

Affiliations

  • 1 Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
  • 2 Driskill Graduate Program in Life Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
  • 3 Department of Biomedical Engineering, Boston University, Boston, MA 02215.
  • 4 Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
  • 5 Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
  • 6 Robert H. Lurie Comprehensive Cancer Center, Chicago, IL 60611.
  • 7 Bindley Bioscience Center, Purdue University, West Lafayette, IN 47906.
  • 8 Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095.
  • 9 Department of Medicine, Los Angeles VA Medical Center, Los Angeles, CA 90095.
  • 10 Department of Electrical and Computer Engineering, Boston University, Boston, MA 02215.
  • 11 Photonics Center, Boston University, Boston, MA 02215.
  • 12 Department of Medicine, Jesse Brown VA Medical Center, Chicago, IL 60612.
PMID: 36197994 DOI: 10.1073/pnas.2203480119
Abstract

Fatty acids are an important source of energy and a key component of Phospholipids in membranes and organelles. Saturated fatty acids (SFAs) are converted into unsaturated fatty acids (UFAs) by stearoyl Co-A desaturase (SCD), an Enzyme active in Cancer. Here, we studied how the dynamics between SFAs and UFAs regulated by SCD impacts ovarian Cancer cell survival and tumor progression. SCD depletion or inhibition caused lower levels of UFAs vs. SFAs and altered fatty acyl chain plasticity, as demonstrated by lipidomics and stimulated Raman scattering (SRS) microscopy. Further, increased levels of SFAs resulting from SCD knockdown triggered endoplasmic reticulum (ER) stress response with brisk activation of IRE1α/XBP1 and PERK/eIF2α/ATF4 axes. Disorganized ER membrane was visualized by electron microscopy and SRS imaging in ovarian Cancer cells in which SCD was knocked down. The induction of long-term mild ER stress or short-time severe ER stress by the increased levels of SFAs and loss of UFAs led to cell death. However, ER stress and Apoptosis could be readily rescued by supplementation with UFAs and reequilibration of SFA/UFA levels. The effects of SCD knockdown or inhibition observed in vitro translated into suppression of intraperitoneal tumor growth in ovarian Cancer xenograft models. Furthermore, a combined intervention using an SCD inhibitor and an SFA-enriched diet initiated ER stress in tumors growing in vivo and potently blocked their dissemination. In all, our data support SCD as a key regulator of the Cancer cell fate under metabolic stress and point to treatment strategies targeting the lipid balance.

Keywords

ER stress; SRS imaging; fatty acids; lipid metabolism; ovarian cancer.

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