Targeting cytochrome P450-dependent cancer cell mitochondria: cancer associated CYPs and where to find them

Guo, Zhijun; Johnson, Veronica; Barrera, Jaime; Porras, Mariel; Hinojosa, Diego; Hernandez, Irwin; McGarrah, Patrick Walsh; Potter, David A.

doi:10.1007/s10555-018-9749-6

Cited by 31 publications

(18 citation statements)

References 104 publications

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“…As mentioned above, sEH hydrolyzes EETs to corresponding diols [Jiang et al, 2005;Harris and Hammock, 2013]. Previous studies reported that EETs stimulate proliferation activity and inhibit apoptosis via activation of ERK1/2 and PI3K/Atk pathways [Yang et al, 2007;Dhanasekaran et al, 2008;Shen et al, 2008;Batchu et al, 2011;Guo et al, 2018]. Contrary to the studies mentioned above, it has been proven that EETs decreased the proliferation of murine fibroblasts [Nieves and Moreno, 2007;Sirish et al, 2013].…”

Section: Discussionmentioning

confidence: 93%

Soluble Epoxide Hydrolase as an Important Player in Intestinal Cell Differentiation

Čížková

Koubova

Foltynkova

et al. 2020

Cells Tissues Organs

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There is growing evidence that soluble epoxide hydrolase (sEH) may play a role in cell differentiation. sEH metabolizes biologically highly active and generally cytoprotective epoxyeicosatrienoic acids (EETs), generated from arachidonic acid metabolism by CYP epoxygenases (CYP2C and CYP2J subfamilies), to less active corresponding diols. We investigated the effect of sEH inhibitor (TPPU) on the expression of villin, CYP2C8, CYP2C9, CYP2J2, and sEH in undifferentiated and in vitro differentiated HT-29 and Caco2 cell lines. The administration of 10 μM TPPU on differentiated HT-29 and Caco2 cells resulted in a significant decrease in expression of villin, a marker for intestinal cell differentiation. It was accompanied by a disruption of the brush border when microvilli appeared sparse and short in atomic force microscope scans of HT-29 cells. Although inhibition of sEH in differentiated HT-29 and Caco2 cells led to an increase in sEH expression in both cell lines, this treatment had an opposite effect on CYP2J2 expression in HT-29 and Caco2 cells. In addition, tissue samples of colorectal carcinoma and adjacent normal tissues from 45 patients were immunostained for sEH and villin. We detected a significant decrease in the expression of both proteins in colorectal carcinoma in comparison to adjacent normal tissue, and the decrease in both sEH and villin expression revealed a moderate positive association. Taken together, our results showed that sEH is an important player in intestinal cell differentiation.

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Section: Discussionmentioning

confidence: 93%

Soluble Epoxide Hydrolase as an Important Player in Intestinal Cell Differentiation

Čížková

Koubova

Foltynkova

et al. 2020

Cells Tissues Organs

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“…These genes, which signi cantly varied within the three phenotypes, possibly contributed to form the heterogenous TIME of HCC. In addition, many genes have been reported to be critical in immune response, such as CD27, CD8A, GZMA and IL7R [46][47][48][49]. The GO and KEGG annotation also displayed intensive immune phenotypes ( Figure S6A-S6B, Table S10-S11).…”

Section: Methylation Modi Cation and Regulation Of The Time Phenotypesmentioning

confidence: 96%

A Novel Immune Classification Reveals Distinct Immune Escape Mechanism and Genomic Alterations: Implications for Immunotherapy in Hepatocellular Carcinoma

Zhang

Shi

Zhou

et al. 2020

Preprint

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BackgroundThe tumor immunological microenvironment (TIME) has a prominent impact on prognosis and immunotherapy. However, the heterogeneous TIME and the mechanisms by which TIME affects immunotherapy have not been elucidated in hepatocellular carcinoma (HCC).MethodsA total of 2195 eligible HCC patients from TCGA and GEO database were collected. We comprehensively explored the different heterogeneous TIME phenotypes and its clinical significance. The potential immune escape mechanisms and what genomic alterations may drive the formation of different phenotypes were further investigated.ResultsWe identified three phenotypes in HCC: TIME-1, the “immune-deficiency” phenotype, with immune cell depletion and proliferation; TIME-2, the “immune-suppressed” phenotype, with being in immunosuppressive states; TIME-3, the “immune-activated phenotype”, with abundant leukocytes infiltration and immune activation. The prognosis and sensitivity to both sorafenib and immunotherapy differed among the three phenotypes. We also underlined the potential immune escape mechanisms: lack of leukocytes and defective tumor antigen presentation capacity in TIME-1, increased immunosuppressive cells in TIME-2, and rich in immunoinhibitory molecules in TIME-3. The different phenotypes also demonstrated specific genomic events: TIME-1 characterized by TP53, CDKN2A, CTNNB1, AXIN1 and FOXD4 alterations; TIME-2 characterized by significant alteration patterns in the PI3K pathway; TIME-3 characterized by ARID1A mutation. Besides, the TIME index (TI) was proposed to quantify TIME infiltration pattern, and it was a superior prognostic and immunotherapy predictor. ConclusionsWe identified three TIME phenotypes with different clinical outcomes, immune escape mechanisms and genomic alterations in HCC, which could present strategies for improving the efficacy of immunotherapy. TI as a novel prognostic and immunotherapeutic signature that could guide personalized immunotherapy and clinical management of HCC.

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Section: Methylation Modi Cation and Regulation Of The Time Phenotypesmentioning

confidence: 98%

A Novel Immune Classification Reveals Distinct Immune Escape Mechanism and Genomic Alterations: Implications for Immunotherapy in Hepatocellular Carcinoma

Zhang

Shi

Zhou

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: The tumor immunological microenvironment (TIME) has a prominent impact on prognosis and immunotherapy. However, the heterogeneous TIME and the mechanisms by which TIME affects immunotherapy have not been elucidated in hepatocellular carcinoma (HCC).Methods: A total of 2195 eligible HCC patients from TCGA and GEO database were collected. We comprehensively explored the different heterogeneous TIME phenotypes and its clinical significance. The potential immune escape mechanisms and what genomic alterations may drive the formation of different phenotypes were further investigated.Results: We identified three phenotypes in HCC: TIME-1, the “immune-deficiency” phenotype, with immune cell depletion and proliferation; TIME-2, the “immune-suppressed” phenotype, with being in immunosuppressive states; TIME-3, the “immune-activated phenotype”, with abundant leukocytes infiltration and immune activation. The prognosis and sensitivity to both sorafenib and immunotherapy differed among the three phenotypes. We also underlined the potential immune escape mechanisms: lack of leukocytes and defective tumor antigen presentation capacity in TIME-1, increased immunosuppressive cells in TIME-2, and rich in immunoinhibitory molecules in TIME-3. The different phenotypes also demonstrated specific genomic events: TIME-1 characterized by TP53, CDKN2A, CTNNB1, AXIN1 and FOXD4 alterations; TIME-2 characterized by significant alteration patterns in the PI3K pathway; TIME-3 characterized by ARID1A mutation. Besides, the TIME index (TI) was proposed to quantify TIME infiltration pattern, and it was a superior prognostic and immunotherapy predictor. A pipeline was developed to classify single patient into one of these three subtypes and calculated the TI. Conclusions: We identified three TIME phenotypes with different clinical outcomes, immune escape mechanisms and genomic alterations in HCC, which could present strategies for improving the efficacy of immunotherapy. TI as a novel prognostic and immunotherapeutic signature that could guide personalized immunotherapy and clinical management of HCC.

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Targeting cytochrome P450-dependent cancer cell mitochondria: cancer associated CYPs and where to find them

Cited by 31 publications

References 104 publications

Soluble Epoxide Hydrolase as an Important Player in Intestinal Cell Differentiation

Soluble Epoxide Hydrolase as an Important Player in Intestinal Cell Differentiation

A Novel Immune Classification Reveals Distinct Immune Escape Mechanism and Genomic Alterations: Implications for Immunotherapy in Hepatocellular Carcinoma

A Novel Immune Classification Reveals Distinct Immune Escape Mechanism and Genomic Alterations: Implications for Immunotherapy in Hepatocellular Carcinoma

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