The Deubiquitinating Enzyme UCHL1 Induces Resistance to Doxorubicin in HER2+ Breast Cancer by Promoting Free Fatty Acid Synthesis

Lu, Guangxian; Li, Jianhua; Ding, Leyun; Wang, Chenping; Tang, Lian; Liu, Xin; Xu, Jinhui; Zhou, Qin; Sun, Jiantong; Wang, Wenjuan; Ding, Xinyuan

doi:10.3389/fonc.2021.629640

Cited by 5 publications

(6 citation statements)

References 33 publications

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“…Proteins enriched in EVs from women with obesity relative to women of a healthy weight are, for the most part, poorly characterized in the context of obesity and/or breast cancer. AKAP2 has been shown to be upregulated in ovarian cancer and promote cancer cell growth 45 , while UCHL1 has been shown to promote cancer stemness and chemoresistance 46,47 . Our in vitro and in vivo results point to a role for O-EVs in tumor progression.…”

Section: Discussionmentioning

confidence: 99%

Breast adipose tissue-derived extracellular vesicles from women with obesity stimulate mitochondrial-induced dysregulated tumor cell metabolism

Liu

Benito-Martín

Vatter

et al. 2023

Preprint

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Breast adipose tissue is an important contributor to the obesity-breast cancer link. Dysregulated cell metabolism is now an accepted hallmark of cancer. Extracellular vesicles (EVs) are nanosized particles containing selective cargo, such as miRNAs, that act locally or circulate to distant sites to modulate target cell functions. Here, we found that long-term education of breast cancer cells (MCF7, T47D) with EVs from breast adipose tissue of women who are overweight or obese (O-EVs) leads to sustained increased proliferative potential. RNA-Seq of O-EV-educated cells demonstrates increased expression of genes, such as ATP synthase and NADH: ubiquinone oxidoreductase, involved in oxidative phosphorylation. O-EVs increase respiratory complex protein expression, mitochondrial density, and mitochondrial respiration in tumor cells. Mitochondrial complex I inhibitor, metformin, reverses O-EV-induced cell proliferation. Several miRNAs, miR-155-5p, miR-10a-3p, and miR-30a-3p, which promote mitochondrial respiration and proliferation, are enriched in O-EVs relative to EVs from lean women. O-EV-induced proliferation and mitochondrial activity are associated with stimulation of the Akt/mTOR/P70S6K pathway, and are reversed upon silencing of P70S6K. This study reveals a new facet of the obesity-breast cancer link with human breast adipose tissue-derived EVs causing the metabolic reprogramming of ER+ breast cancer cells.

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Section: Discussionmentioning

confidence: 99%

Breast adipose tissue-derived extracellular vesicles from women with obesity stimulate mitochondrial-induced dysregulated tumor cell metabolism

Liu

Benito-Martín

Vatter

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Proteins enriched in EVs from women with obesity relative to women of a healthy weight are, for the most part, poorly characterized in the context of obesity and/or breast cancer. AKAP2 has been shown to be upregulated in ovarian cancer and promote cancer cell growth (Li et al , 2017), while UCHL1 has been shown to promote cancer stemness and chemoresistance (Lu et al , 2021; Tian et al , 2022). Our in vitro and in vivo results point to a role for O‐EVs in tumor progression.…”

Section: Discussionmentioning

confidence: 99%

Breast adipose tissue‐derived extracellular vesicles from obese women alter tumor cell metabolism

Liu,

Benito‐Martin,

Pelissier Vatter

et al. 2023

EMBO Reports

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Breast adipose tissue is an important contributor to the obesity–breast cancer link. Extracellular vesicles (EVs) are nanosized particles containing selective cargo, such as miRNAs, that act locally or circulate to distant sites to modulate target cell functions. Here, we find that long‐term education of breast cancer cells with EVs obtained from breast adipose tissue of women who are overweight or obese (O‐EVs) results in increased proliferation. RNA‐seq analysis of O‐EV‐educated cells demonstrates increased expression of genes involved in oxidative phosphorylation, such as ATP synthase and NADH: ubiquinone oxidoreductase. O‐EVs increase respiratory complex protein expression, mitochondrial density, and mitochondrial respiration in tumor cells. The mitochondrial complex I inhibitor metformin reverses O‐EV‐induced cell proliferation. Several miRNAs—miR‐155‐5p, miR‐10a‐3p, and miR‐30a‐3p—which promote mitochondrial respiration and proliferation, are enriched in O‐EVs relative to EVs from lean women. O‐EV‐induced proliferation and mitochondrial activity are associated with stimulation of the Akt/mTOR/P70S6K pathway, and are reversed upon silencing of P70S6K. This study reveals a new facet of the obesity‐breast cancer link with human breast adipose tissue‐derived EVs causing metabolic reprogramming of breast cancer cells.

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“…Several agents that target specific metabolic pathways, including fatty acid synthesis, have been shown to have the therapeutic potential to improve cancer treatment efficacy. A reduction of key enzymes in the DNL pathway has been shown to cause a reduction in fatty acid products [27] and fatty acid oxidation (FAO) [12], resulting in a decrease in the proliferative, metastatic and invasive ability of cancer cells [67][68][69][70][71][72][73][74][75][76]. The mechanism of the anticancer effect of EGCG has been demonstrated to be mediated via inhibiting the fatty acid biosynthesis pathway [50,[77][78][79][80].…”

Section: Discussionmentioning

confidence: 99%

Epigallocatechin gallate triggers apoptosis by suppressing de novo lipogenesis in colorectal carcinoma cells

et al. 2022

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The de novo lipogenesis (DNL) pathway has been identified as a regulator of cancer progression and aggressiveness. Downregulation of key lipogenesis enzymes has been shown to activate apoptosis in cancerous cells. Epigallocatechin gallate (EGCG) inhibits cancer cell proliferation without causing cytotoxicity in healthy cells. The present study aimed to investigate the effects of EGCG on the promotion of apoptosis associated with the DNL pathway inhibition in cancer cells, both in vitro and in vivo. We observed that two colorectal cancer cell lines (HCT116 and HT‐29) had a higher cytotoxic response to EGCG treatment than hepatocellular carcinoma cells, including HepG2 and HuH‐7. EGCG treatment decreased cell viability and increased mitochondrial damage‐triggered apoptosis in both HCT116 and HT‐29 cancer cells. Additionally, we treated mice transplanted with HCT116 cells with 30 or 50 mg·kg−1 EGCG for 7 days to evaluate the apoptotic effects of EGCG treatment in a xenograft mouse model of cancer. We observed a decrease in intracellular fatty acid levels, which suggested that EGCG‐induced apoptosis was associated with a decrease in fatty acid levels in cancer. Suppression of ATP synthesis by EGCG indicated that cell death induction in cancer cells could be mediated by shared components of the DNL and energy metabolism pathways. In addition, EGCG‐induced apoptosis suppressed the expression of the phosphorylation protein kinase B and extracellular signal‐regulated kinase 1/2 signaling proteins in tumors from xenografted mice. Cytotoxic effects in unaffected organs and tissues of the mouse xenograft model were absent upon EGCG treatment.

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The Deubiquitinating Enzyme UCHL1 Induces Resistance to Doxorubicin in HER2+ Breast Cancer by Promoting Free Fatty Acid Synthesis

Cited by 5 publications

References 33 publications

Breast adipose tissue-derived extracellular vesicles from women with obesity stimulate mitochondrial-induced dysregulated tumor cell metabolism

Breast adipose tissue-derived extracellular vesicles from women with obesity stimulate mitochondrial-induced dysregulated tumor cell metabolism

Breast adipose tissue‐derived extracellular vesicles from obese women alter tumor cell metabolism

Epigallocatechin gallate triggers apoptosis by suppressing de novo lipogenesis in colorectal carcinoma cells

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