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

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.

SUBMITTER: Xiong X

PROVIDER: S-EPMC9525627 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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

Xiong Xiaopeng X Hasani Sumati S Young Lyndsay E A LEA Rivas Dylan R DR Skaggs Ashley T AT Martinez Rebecca R Wang Chi C Weiss Heidi L HL Gentry Matthew S MS Sun Ramon C RC Gao Tianyan T

Cell death and differentiation 20220324 10

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 s ...[more]

PMID: 35332310

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Project description:Understanding the complex interplay between tumor biology and host metabolism presents a formidable challenge with important clinical implications. At the local level, metabolic alterations of tumor cells and tumor microenvironment is a well-recognized process and constitute one of the major hallmarks of cancer cells. Consequently, research has largely isolated tumor biology from systemic metabolic dynamics, overlooking their potential interrelation. Nonetheless, cancer pathology is also very clearly associated with broad systemic metabolic disturbances, as exemplified by the frequent development of cachexia, which reaches up to 40% of colon cancer (CC) patients. Other metabolic alterations observed associated with cancer include insulin resistance, hypercalcemia, and amino acid metabolism, which underline the extensive systemic impact of cancer on the metabolic networks. In addition to these alterations, another interesting yet less studied phenomenon in cancer pathology is the observation that cancer patients present alterations of their typical fatty acid profiles in circulation. Evidence of this phenomenon is limited and scattered across the literature, although some studies have identified this alteration in patients with colorectal and liver cancer. Nonetheless, discerning whether these lipid profile shifts signify an intrinsic metabolic alteration or are secondary to factors such as malnutrition, adipose tissue dynamics, or clinical parameters like tumor staging and location has yet to be determined. It is evident that addressing this issue requires a more comprehensive analysis of the possible factors involved. Our study adopted an integrative methodology to study this process in CC, combining advanced body composition analysis, nutritional assessments, extensive clinical and transcriptomic data of the tumor, and precise profiling of esterified fatty acids in plasma. This multifaceted strategy has enabled us to confirm that the alteration of FA levels is a frequent phenomenon in patients with CC.

Project description:Aminoglycoside antibiotics rely on the proton motive force to enter the bacterial cell, and facultative anaerobes like Staphylococcus aureus can shift energy generation from respiration to fermentation, becoming tolerant of aminoglycosides. Following this metabolic shift, high concentrations of aminoglycosides are required to eradicate S. aureus infections, which endangers the host due to the toxicity of aminoglycosides. Membrane-disrupting molecules prevent aminoglycoside tolerance in S. aureus by facilitating passive entry of the drug through the membrane. Polyunsaturated fatty acids (PUFAs) increase membrane permeability when incorporated into S. aureus. Here, we report that the abundant host-derived PUFA arachidonic acid increases the susceptibility of S. aureus to aminoglycosides, decreasing the aminoglycoside concentration needed to kill S. aureus. We demonstrate that PUFAs and aminoglycosides synergize to kill multiple strains of S. aureus, including both methicillin-resistant and -susceptible S. aureus. We also present data showing that PUFAs and aminoglycosides effectively kill S. aureus small colony variants, strains that are particularly recalcitrant to killing by many antibiotics. We conclude that cotreatment with PUFAs, which are molecules with low host toxicity, and aminoglycosides decreases the aminoglycoside concentration necessary to kill S. aureus, lowering the toxic side effects to the host associated with prolonged aminoglycoside exposure. IMPORTANCE Staphylococcus aureus infects every niche of the human host, and these infections are the leading cause of Gram-positive sepsis. Aminoglycoside antibiotics are inexpensive, stable, and effective against many bacterial infections. However, S. aureus can shift its metabolism to become tolerant of aminoglycosides, requiring increased concentrations and/or longer courses of treatment, which can cause severe host toxicity. Here, we report that polyunsaturated fatty acids (PUFAs), which have low host toxicity, disrupt the S. aureus membrane, making the pathogen susceptible to aminoglycosides. Additionally, cotreatment with aminoglycosides is effective at killing S. aureus small colony variants, strains that are difficult to treat with antibiotics. Taken together, the data presented herein show the promise of PUFA cotreatment to increase the efficacy of aminoglycosides against S. aureus infections and decrease the risk to the human host of antibiotic-induced toxicity.

Dataset Information

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

Publications

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

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