ASS1 enhances anoikis resistance via AMPK/CPT1A-mediated fatty acid metabolism in ovarian cancer

Xu Feng; Zhaodong Ji; Xiaoxi Fan; Yue Kong; Yinjue Yu; Yang Shao; Jiao Meng; Xiaoyan Zhou; Ranran Tang; Chunxia Ren; Gong Yang

doi:10.1016/j.canlet.2024.217082

ASS1 enhances anoikis resistance via AMPK/CPT1A-mediated fatty acid metabolism in ovarian cancer

Cancer Lett. 2024 Jun 22:217082. doi: 10.1016/j.canlet.2024.217082. Online ahead of print.

Authors

Xu Feng¹, Zhaodong Ji², Xiaoxi Fan¹, Yue Kong³, Yinjue Yu⁴, Yang Shao¹, Jiao Meng¹, Xiaoyan Zhou¹, Ranran Tang⁵, Chunxia Ren⁶, Gong Yang⁷

Affiliations

¹ Cancer Institute & Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
² Cancer Institute & Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Department of Laboratory Medicine, Huashan Hospital, Shanghai Medical School, Fudan University, Shanghai, China.
³ Cancer Institute & Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Center for Reproductive Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
⁴ Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Central Laboratory, The Fifth People's Hospital of Shanghai Fudan University, Shanghai, China.
⁵ Nanjing Medical Research Center for Women and Children, Women's Hospital of Nanjing Medical University, Nanjing Women and Children's Healthcare Hospital, Nanjing, China. Electronic address: [email protected].
⁶ Center for Reproductive Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China. Electronic address: [email protected].
⁷ Cancer Institute & Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Central Laboratory, The Fifth People's Hospital of Shanghai Fudan University, Shanghai, China. Electronic address: [email protected].

PMID: 38914306
DOI: 10.1016/j.canlet.2024.217082

Abstract

Metastasis is the leading cause of death in ovarian carcinoma (OC), whereas anoikis resistance is a critical step for the survival of the detached OC cells. Despite extensive research, targeting anoikis resistance remains a challenge. Here, we first identified that argininosuccinate synthase 1 (ASS1), a key enzyme in urea cycle markedly upregulated in OC cells of detached culture, is associated with increased anoikis resistance and metastasis. Disruption of the AMP/ATP balance by overexpressing ASS1 activates AMPK and the downstream factor CPT1A. Then, we further found that ASS1 enhances FAO, leading to higher ATP generation and lipid utilization. Inhibition of CPT1A reverses the ASS1-induced FAO, which interrupts the AMP/ATP balance and the activation of AMPK. These results extend ASS1's relevance beyond nitrogen and fatty acid metabolisms, and may provide some new insights into OC metabolism and represent a shift from traditional views. In conclusion, our study reveals a mechanism that the ASS1/AMPK/CPT1A axis is crucial for anoikis resistance and metastasis, which may open up a new avenue for the intervention of OC.

Keywords: ASS1; Anoikis resistance; CPT1A; Fatty acid oxidation; Ovarian cancer.