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.
| Original language | English (US) |
|---|---|
| Article number | e2203480119 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 119 |
| Issue number | 41 |
| DOIs | |
| State | Published - Oct 11 2022 |
Funding
This work was supported by grant R01 CA224275 to D.M. and J.X.C. and grant R33 CA223581 and NSF CHE1807106 grant to J.X.C. We thank Drs. Debabrata Chakravarti and Navdeep Chandel for valuable comments. Tumor specimens were procured through the Pathology Core, and sequencing was performed in the NUSeq Core supported by NCI CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. Lipidomics analysis was performed in Metabolite Profiling Facility at Bindley Bioscience Center, Purdue University. TEM was performed in the Center for Advanced Microscopy/Nikon Imaging Center (CAM) at Northwestern University supported by NCI grant CA060553. IncuCyte imaging was performed in the Analytical bioNanoTechnology Core Facility of the Simpson Querrey Institute for BioNanotechnology at Northwestern University (NSF grant ECCS-2025633). Flow cytometry analysis of ferroptosis was supported by the Northwestern University \u2013 Flow Cytometry Core Facility supported by Cancer Center Support Grant (NCI grant CA060553). This research was supported in part through the computational resources and staff contributions provided for the Quest high-performance computing facility at Northwestern University which is jointly supported by the Office of the Provost, the Office for Research, and Northwestern University Information Technology. ACKNOWLEDGMENTS. This work was supported by grant R01 CA224275 to D.M. and J.X.C. and grant R33 CA223581 and NSF CHE1807106 grant to J.X.C. We thank Drs. Debabrata Chakravarti and Navdeep Chandel for valuable comments. Tumor specimens were procured through the Pathology Core, and sequencing was performed in the NUSeq Core supported by NCI CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. Lipido-mics analysis was performed in Metabolite Profiling Facility at Bindley Bioscience Center, Purdue University. TEM was performed in the Center for Advanced Microscopy/Nikon Imaging Center (CAM) at Northwestern University supported by NCI grant CA060553. IncuCyte imaging was performed in the Analytical bioNanoTechnology Core Facility of the Simpson Querrey Institute for BioNano-technology at Northwestern University (NSF grant ECCS-2025633). Flow cytometry analysis of ferroptosis was supported by the Northwestern University \u2013 Flow Cytometry Core Facility supported by Cancer Center Support Grant (NCI grant CA060553). This research was supported in part through the computational resources and staff contributions provided for the Quest high-performance computing facility at Northwestern University which is jointly supported by the Office of the Provost, the Office for Research, and Northwestern University Information Technology.
Keywords
- ER stress
- SRS imaging
- fatty acids
- lipid metabolism
- ovarian cancer
ASJC Scopus subject areas
- General
