A link between lipid metabolism and epithelial-mesenchymal transition provides a target for colon cancer therapy

Martínez, Rubén; Cruz-Gil, Silvia; Cedrón, Marta Gómez de; Álvarez-Fernández, Mónica; Vargas, Teodoro; Molina, Susana; García, Belén Prieto; Herránz, Jesús; Moreno-Rubio, Juan; Reglero, Guillermo; Pérez-Moreno, Mirna; Feliú, Jaime; Malumbres, Marcos; Molina, Ana Ramı́rez de

doi:10.18632/oncotarget.5340

Cited by 121 publications

(128 citation statements)

References 57 publications

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“…In summary, in this study T/T genotype for rs8086 is associated with worse clinical outcome acting as a “risk genotype” in these CC patients and simultaneously correlates with high ACSL1 mRNA levels, which in turn had previously been associated also with worse clinical outcome in these patients [11] probably mediated by the induction of an invasive phenotype [10]. …”

Section: Discussionmentioning

confidence: 88%

“…With respect to the analysis of the influence of the 57 analyzed SNPs on the DFS, the results showed a robust association for rs8086 and rs522951 (Table 3; Fig 1) between DFS of the patients and genotype for these polymorphisms within ACSL1 and SCD respectively, genes that codify for two enzymes that have been recently described as a LM driving-force in colon cancer progression [10]. …”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, we have found that LM activation specifically through Acyl-CoA synthetase/ Stearoyl-CoA desaturase ACSL/SCD network, is associated to CC patient relapse due to phenotypic plasticity associated to this metabolic reprogramming [10–12]. …”

Section: Introductionmentioning

confidence: 99%

“…In this regard, in our recent analysis of LM alterations associated to CC progression, we identify a gene expression signature of 4 LM-related genes (ColoLipidGene) with a strongly marked role in stage II CC patients prognosis [11]. We observed that the combined activation of lipid transport through ABCA1 (ATP-Binding Cassette Subfamily-A Member 1 ( ABCA1 [MIM: +600046]), lipid activation through ACSL1 and AGPAT1 (Acyl-CoA Synthetase Long Chain Family, Member 1 ( ACSL1 [MIM: *152425]), 1-Acylglycerol-3-Phosphate O-Acyltransferase 1 ( AGPAT1 [MIM: *603099]) and lipid-related toxicity drainage through SCD (Stearoyl-Coa Desaturase ( SCD [MIM: *604031]) might confer an energetic advantage to the tumoral cell resulting in the promotion of tumor progression and relapse [10–12]. …”

Section: Introductionmentioning

confidence: 99%

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3’UTR Polymorphism in ACSL1 Gene Correlates with Expression Levels and Poor Clinical Outcome in Colon Cancer Patients

et al. 2016

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Strong evidence suggests that lipid metabolism (LM) has an essential role in tumor growth to support special energetic and structural requirements of tumor cells. Recently, overexpression of LM-related genes, apolipoproteins related to metabolic syndrome, and ACSL/SCD network involved in fatty acid activation have been proposed as prognostic markers of colon cancer (CC). Furthermore, activation of this latter lipid network has been recently demonstrated to confer invasive and stem cell properties to tumor cells promoting tumor aggressiveness and patient relapse. With the aim of elucidating whether any genetic variation within these genes could influence basal expression levels and consequent susceptibility to relapse, we genotype, in 284 CC patients, 57 polymorphisms located in the 7 genes of these lipid networks previously associated with worse clinical outcome of CC patients (ABCA1, ACSL1, AGPAT1, APOA2, APOC1, APOC2 and SCD), some of them related to CC aggressiveness. After adjusting with clinical confounding factors and multiple comparisons, an association between genotype and disease-free survival (DFS) was shown for rs8086 in 3’-UTR of ACSL1 gene (HR 3.08; 95% CI 1.69–5.63; adjusted p = 0.046). Furthermore, the risk T/T genotype had significantly higher ACSL1 gene expression levels than patients carrying C/T or C/C genotype (means = 5.34; 3.73; 2.37 respectively; p-value (ANOVA) = 0.019), suggesting a functional role of this variant. Thus, we have identified a “risk genotype” of ACSL1 gene that confers constitutive high levels of the enzyme, which is involved in the activation of fatty acids through conversion to acyl-CoA and has been recently related to increased invasiveness of tumor cells. These results suggest that rs8086 of ACSL1 could be a promising prognostic marker in CC patients, reinforcing the relevance of LM in the progression of CC.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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3’UTR Polymorphism in ACSL1 Gene Correlates with Expression Levels and Poor Clinical Outcome in Colon Cancer Patients

et al. 2016

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“…ROS can be generated by different mechanisms such as exposure to matrix metalloproteinases (MMPs; Radisky et al ., 2005), inflammation (Coussens and Werb, 2002), and as a result of byproducts of cell metabolism. In this sense, a role of carbohydrates in the induction of EMT has been described (Lin et al ., 2012), and we recently have reported a role of lipid metabolism‐related genes in the induction of EMT in colon cancer cell lines (Sanchez‐Martinez et al ., 2015). …”

Section: Discussionmentioning

confidence: 99%

MicroRNA‐661 modulates redox and metabolic homeostasis in colon cancer

et al. 2017

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Cancer cell survival and metastasis are dependent on metabolic reprogramming that is capable of increasing resistance to oxidative and energetic stress. Targeting these two processes can be crucial for cancer progression. Herein, we describe the role of microRNA‐661 (miR661) as epigenetic regulator of colon cancer (CC) cell metabolism. MicroR661 induces a global increase in reactive oxygen species, specifically in mitochondrial superoxide anions, which appears to be mediated by decreased carbohydrate metabolism and pentose phosphate pathway, and by a higher dependency on mitochondrial respiration. MicroR661 overexpression in non‐metastatic human CC cells induces an epithelial‐to‐mesenchymal transition phenotype, and a reduced tolerance to metabolic stress. This seems to be a general effect of miR661 in CC, since metastatic CC cell metabolism is also compromised upon miR661 overexpression. We propose hexose‐6‐phosphate dehydrogenase and pyruvate kinase M2 as two key players related to the observed metabolic reprogramming. Finally, the clinical relevance of miR661 expression levels in stage‐II and III CC patients is discussed. In conclusion, we propose miR661 as a potential modulator of redox and metabolic homeostasis in CC.

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ABCA1 overexpression worsens colorectal cancer prognosis by facilitating tumour growth and caveolin‐1‐dependent invasiveness, and these effects can be ameliorated using the BET inhibitor apabetalone

et al. 2018

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At the time of diagnosis, 20% of patients with colorectal cancer present metastasis. Among individuals with primary lesions, 50% of them will develop distant tumours with time. Therefore, early diagnosis and prediction of aggressiveness is crucial for therapy design and disease prognosis. Tumoral cells must undergo significant changes in energy metabolism to meet increased structural and energetic demands for cell proliferation, and metabolic alterations are considered to be a hallmark of cancer. Here, we present the ATP‐binding cassette transporter (ABCA1), a regulator of cholesterol transport, as a new marker for invasion and colorectal cancer survival. ABCA1 is significantly overexpressed in patients at advanced stages of colorectal cancer, and its overexpression confers proliferative advantages together with caveolin‐1 dependent‐increased migratory and invasive capacities. Thus, intracellular cholesterol imbalances mediated by ABCA1 overexpression may contribute to primary tumour growth and dissemination to distant locations. Furthermore, we demonstrate here that increased levels of apolipoprotein A1 (APOA1), a protein involved in cholesterol efflux and high‐density lipoprotein constitution, in the extracellular compartment modulates expression of ABCA1 by regulating COX‐2, and compensate for ABCA1‐dependent excessive export of cholesterol. APOA1 emerges as a new therapeutic option to inhibit the promotion of colorectal cancer to metastasis by modulating intracellular cholesterol metabolism. Furthermore, we propose apabetalone, an orally available small molecule that is currently being evaluated in clinical trials for the treatment of atherosclerosis, as a new putative therapeutic option to prevent colorectal cancer progression by increasing APOA1 expression and regulating reverse transport of cholesterol.

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A link between lipid metabolism and epithelial-mesenchymal transition provides a target for colon cancer therapy

Cited by 121 publications

References 57 publications

3’UTR Polymorphism in ACSL1 Gene Correlates with Expression Levels and Poor Clinical Outcome in Colon Cancer Patients

3’UTR Polymorphism in ACSL1 Gene Correlates with Expression Levels and Poor Clinical Outcome in Colon Cancer Patients

MicroRNA‐661 modulates redox and metabolic homeostasis in colon cancer

ABCA1 overexpression worsens colorectal cancer prognosis by facilitating tumour growth and caveolin‐1‐dependent invasiveness, and these effects can be ameliorated using the BET inhibitor apabetalone

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