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Activation of Drp1 promotes fatty acids-induced metabolic reprograming to potentiate Wnt signaling in colon cancer

Cell Death & Differentiation volume 29, pages 1913–1927 (2022)Cite this article

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Abstract

Cancer cells are known for their ability to adapt variable metabolic programs depending on the availability of specific nutrients. Our previous studies have shown that uptake of fatty acids alters cellular metabolic pathways in colon cancer cells to favor fatty acid oxidation. Here, we show that fatty acids activate Drp1 to promote metabolic plasticity in cancer cells. Uptake of fatty acids (FAs) induces mitochondrial fragmentation by promoting ERK-dependent phosphorylation of Drp1 at the S616 site. This increased phosphorylation of Drp1 enhances its dimerization and interaction with Mitochondrial Fission Factor (MFF) at the mitochondria. Consequently, knockdown of Drp1 or MFF attenuates fatty acid-induced mitochondrial fission. In addition, uptake of fatty acids triggers mitophagy via a Drp1- and p62-dependent mechanism to protect mitochondrial integrity. Moreover, results from metabolic profiling analysis reveal that silencing Drp1 disrupts cellular metabolism and blocks fatty acid-induced metabolic reprograming by inhibiting fatty acid utilization. Functionally, knockdown of Drp1 decreases Wnt/β-catenin signaling by preventing fatty acid oxidation-dependent acetylation of β-catenin. As a result, Drp1 depletion inhibits the formation of tumor organoids in vitro and xenograft tumor growth in vivo. Taken together, our study identifies Drp1 as a key mediator that connects mitochondrial dynamics with fatty acid metabolism and cancer cell signaling.

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Fig. 1: Fatty acid treatment induces mitochondrial fission in colon cancer cells.
Fig. 2: Fatty acid-induced Drp1 phosphorylation facilitates mitochondrial recruitment of Drp1 via interaction with MFF.
Fig. 3: Knockdown of Drp1 blocks fatty acid-induced mitochondrial fission and fatty acid utilization.
Fig. 4: Knockdown of Drp1 disrupts FAO and alters cellular metabolism in colon cancer cells.
Fig. 5: Uptake of fatty acids induces mitophagy through a Drp1- and p62-dependent mechanism in colon cancer cells.
Fig. 6: Downregulation of Drp1 decreases cellular levels of acetate and acetylation of β-catenin.
Fig. 7: Knockdown of Drp1 inhibits xenograft tumor growth and Wnt signaling in vivo.

Materials availability

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank Dr. Hiromi Sesaki at Johns Hopkins University for kindly providing the Su9-mCherry-GFP expression plasmid and Dr. Yekaterina Zaytseva for sharing the PT130 cell line. The diagram shown in Fig. 7k was created with BioRender.com.

Funding

This work was supported by R01CA133429 (TG), R01CA208343 (TG), F31CA260840 (SH), R35NS116824 (MSG), R01AG066653 (RCS), and a pilot grant from P20GM121327 (University of Kentucky Center for Cancer and Metabolism). ATS is supported by National Science Foundation Graduate Research Fellowship Award (#1839289). The studies were conducted with support provided by the Redox Metabolism, Biospecimen Procurement and Translational Pathology, Flow Cytometry and Immune Monitoring, and Biostatistics and Bioinformatics Shared Resource Facilities of the University of Kentucky Markey Cancer Center (P30CA177558) at the University of Kentucky.

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  1. These authors contributed equally: Xiaopeng Xiong, Sumati Hasani.

Authors and Affiliations

  1. Markey Cancer Center, University of Kentucky, Lexington, KY, 40536-0679, USA

    Xiaopeng Xiong, Dylan R. Rivas, Rebecca Martinez, Chi Wang, Heidi L. Weiss, Ramon C. Sun & Tianyan Gao

  2. Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, 40536-0679, USA

    Sumati Hasani, Lyndsay E. A. Young, Ashley T. Skaggs, Matthew S. Gentry & Tianyan Gao

  3. Department of Neuroscience, University of Kentucky, Lexington, KY, 40536-0679, USA

    Ramon C. Sun

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Contributions

XX, SH, and TG designed all aspects of the study; XX, SH, LEAY, DR, ATS, RM, CW, and HLW performed experiments and analysis; MSG and RCS provided critical support for metabolic analysis; XX, SH, and TG wrote the manuscript.

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Correspondence to Tianyan Gao.

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Xiong, X., Hasani, S., Young, L.E.A. et al. Activation of Drp1 promotes fatty acids-induced metabolic reprograming to potentiate Wnt signaling in colon cancer. Cell Death Differ 29, 1913–1927 (2022). https://doi.org/10.1038/s41418-022-00974-5

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