Tissue cholesterol metabolism and prostate cancer aggressiveness: Ethno‐geographic variations

Lethongsavarn, Vincent; Pinault, Michèle; Diédhiou, Abdoulaye; Guimaraes, Cyrille; Guibon, Roseline; Bruyère, F.; Mathiéu, Romain; Rioux‐Leclercq, Nathalie; Multigner, Luc; Brureau, Laurent; Fournier, Georges; Doucet, Laurent; Blanchet, Pascal; Fromont, Gaëlle

doi:10.1002/pros.24234

Cited by 10 publications

(11 citation statements)

References 43 publications

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“…Through EMT, epithelial cancer cells lose cell polarity and cell–cell adhesion ability, acquire mesenchymal characteristics, and transition from quiescent to malignant forms, which correlate positively with various cancer features, such as migration, invasion, and metastatic potential 24,37 . A previous study revealed that SREBP2 promotes invasion and migration of prostate cancer cells via EMT 38 . Therefore, we speculated that SREBP2 exerts its effects in HCC via EMT.…”

Section: Discussionmentioning

confidence: 93%

LATS‐regulated nuclear‐cytoplasmic translocation of SREBP2 inhibits hepatocellular carcinoma cell migration and invasion via epithelial–mesenchymal transition

Zhang

Gao

et al. 2023

Molecular Carcinogenesis

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Abnormal cholesterol synthesis plays a crucial role in the development of hepatocellular carcinoma (HCC). Sterol regulatory element-binding protein 2 (SREBP2) is involved in cholesterol synthesis by translocating to the nucleus where it stimulates the transcription of genes encoding enzymes involved in the cholesterol synthesis pathway. However, the function and regulatory mechanism of SREBP2 in HCC remain unclear. In this study, we aimed to gain a better understanding of the effects of SREBP2 and its functional mechanism in HCC. In 20 HCC patients, we demonstrated that SREBP2 was highly expressed in HCC specimens, relative to their peritumoral tissue, and that higher expression correlated positively with a poor prognosis in these patients. Moreover, higher SREBP2 levels in the nucleus enhanced the occurrence of microvascular invasion, whereas inhibition of SREBP2 nuclear translocation by fatostatin markedly suppressed the migration and invasion of HCC cells via the epithelial-mesenchymal transition (EMT) process. The effects of SREBP2 were subject to functional activity of large tumor suppressor kinase (LATS), whereas inhibition of LATS promoted nuclear translocation of SREBP2, as observed in hepatoma cells and a subset of subcutaneous tumor samples from nude mice. In conclusion, SREBP2 enhances the invasion and metastasis of HCC cells by promoting EMT, which can be strengthened by the repression of LATS. Therefore, SREBP2 may serve as a novel therapeutic target for HCC.

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Section: Discussionmentioning

confidence: 93%

LATS‐regulated nuclear‐cytoplasmic translocation of SREBP2 inhibits hepatocellular carcinoma cell migration and invasion via epithelial–mesenchymal transition

Zhang

Gao

et al. 2023

Molecular Carcinogenesis

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“…In addition, PPARγ derived PCa growth and metastasis by upregulating AKT3 could increase mitochondrial biogenesis levels [ 59 ]. Studies have found that the amount of cholesterol is higher in PCa cells compared to normal cells, influencing cancer development and progression [ 60 ]. Henrich et al [ 61 ] revealed that reducing cholesterol in bone marrow myeloid cells can render the transduction of PCa extracellular vesicle signaling, thus hindering the bone metastasis of PCa.…”

Section: Discussionmentioning

confidence: 99%

A Novel Four Mitochondrial Respiration-Related Signature for Predicting Biochemical Recurrence of Prostate Cancer

Xia

Liu

Fan

et al. 2023

JCM

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The biochemical recurrence (BCR) of patients with prostate cancer (PCa) after radical prostatectomy is high, and mitochondrial respiration is reported to be associated with the metabolism in PCa development. This study aimed to establish a mitochondrial respiratory gene-based risk model to predict the BCR of PCa. RNA sequencing data of PCa were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, and mitochondrial respiratory-related genes (MRGs) were sourced via GeneCards. The differentially expressed mitochondrial respiratory and BCR-related genes (DE-MR-BCRGs) were acquired through overlapping BCR-related differentially expressed genes (BCR-DEGs) and differentially expressed MRGs (DE-MRGs) between PCa samples and controls. Further, univariate Cox, least absolute shrinkage and selection operator (LASSO), and multivariate Cox analyses were performed to construct a DE-MRGs-based risk model. Then, a nomogram was established by analyzing the independent prognostic factor of five clinical features and risk scores. Moreover, Gene Set Enrichment Analysis (GSEA), tumor microenvironment, and drug susceptibility analyses were employed between high- and low-risk groups of PCa patients with BCR. Finally, qRT-PCR was utilized to validate the expression of prognostic genes. We identified 11 DE-MR-BCRGs by overlapping 132 DE-MRGs and 13 BCR-DEGs and constructed a risk model consisting of 4 genes (APOE, DNAH8, EME2, and KIF5A). Furthermore, we established an accurate nomogram, including a risk score and a Gleason score, for the BCR prediction of PCa patients. The GSEA result suggested the risk model was related to the PPAR signaling pathway, the cholesterol catabolic process, the organic hydroxy compound biosynthetic process, the small molecule catabolic process, and the steroid catabolic process. Simultaneously, we found six immune cell types relevant to the risk model: resting memory CD4+ T cells, monocytes, resting mast cells, activated memory CD4+ T cells, regulatory T cells (Tregs), and macrophages M2. Moreover, the risk model could affect the IC50 of 12 cancer drugs, including Lapatinib, Bicalutamide, and Embelin. Finally, qRT-PCR showed that APOE, EME2, and DNAH8 were highly expressed in PCa, while KIF5A was downregulated in PCa. Collectively, a mitochondrial respiratory gene-based nomogram including four genes and one clinical feature was established for BCR prediction in patients with PCa, which could provide novel strategies for further studies.

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“…To gather a more refined chemical description of cellular states we focus on the lipid fingerprint region and conduct further ATR‐FTIR spectroscopy analysis of lipid extracts of TGF‐β treated cells. Emerging studies linking lipid metabolism with EMT serves as an additional motivation 39–41 …”

Section: Discussionmentioning

confidence: 99%

“…Emerging studies linking lipid metabolism with EMT serves as an additional motivation. [39][40][41] Structural parameters such as saturation, unsaturation, and acyl chain length of fatty acids are estimated from the FTIR spectral peaks at and around 3010, 2954, 2931, 2920, 2870, and 2852 cm −1 which appear consistently in all four samples. Elevated unsaturation index in the treated cells presumably reflects the increased membrane fluidity associated with mesenchymal transition, 42 while decreased acyl chain length is suggestive of an elevated β-oxidation of fatty acids due to a low rate of glycolysis and limited availability of acetyl-CoA characteristic of prostate cancer.…”

Section: Classification Of Pc3 Cells Based On Biochemical and Metabol...mentioning

confidence: 99%

FTIR microspectroscopy and multivariate analysis facilitate identification of dynamic changes in epithelial‐to‐mesenchymal transition induced by TGF‐β in prostate cancer cells

Karmakar

Lahiri

Bedi

et al. 2023

J of Cellular Biochemistry

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The standard diagnosis of prostate cancer is accomplished by the identification of cytomorphological deviations in biopsied tissues while immunohistochemistry is used to resolve the equivocal cases. Accumulating evidence favors the concept that epithelial‐to‐mesenchymal transition (EMT) is a stochastic process composed of multiple intermediate states instead of a single binary switch. Despite its significant role in promoting cancer aggressiveness, the current tissue‐based risk stratification tools do not include any of the EMT phenotypes as a metric. As a proof‐of‐concept, the present study analyzes the temporal progression of EMT in transforming growth factor‐beta (TGF‐β) treated PC3 cells encompassing multifarious characteristics such as morphology, migration and invasion, gene expression, biochemical fingerprint, and metabolic activity. Our multimodal approach reinstates EMT plasticity in TGF‐β treated PC3 cells. Further, it highlights that mesenchymal transition is accompanied by discernible changes in cellular morphometry and molecular signatures particularly in the range of 1800–1600 cm−1 and 3100–2800 cm−1 of Fourier‐transformed infrared (FTIR) spectra signifying Amide III and lipid, respectively. Investigation of attenuated total reflectance (ATR)‐FTIR spectra of extracted lipids from PC3 cell populations undergoing EMT identifies changes in stretching vibration at FTIR peaks at 2852, 2870, 2920, 2931, 2954, and 3010 cm−1 characteristics of fatty acids and cholesterol. Chemometric analysis of these spectra indicates that the level of unsaturation and acyl chain length of fatty acid coregister with differential epithelial/mesenchymal states of TGF‐β treated PC3 cells. Observed changes in lipids also correlate with cellular nicotinamide adenine dinucleotide hydrogen (NADH) and flavin adenine dinucleotide dihydrogen (FADH2) levels and mitochondrial oxygen consumption rate. In summary, our study establishes that morphological and phenotypic traits of epithelial/mesenchymal variants of PC3 cells concur with their respective biochemical and metabolic properties. It also underscores that spectroscopic histopathology has a definitive potential to refine the diagnosis of prostate cancer reckoning its molecular and biochemical heterogeneities.

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Tissue cholesterol metabolism and prostate cancer aggressiveness: Ethno‐geographic variations

Cited by 10 publications

References 43 publications

LATS‐regulated nuclear‐cytoplasmic translocation of SREBP2 inhibits hepatocellular carcinoma cell migration and invasion via epithelial–mesenchymal transition

LATS‐regulated nuclear‐cytoplasmic translocation of SREBP2 inhibits hepatocellular carcinoma cell migration and invasion via epithelial–mesenchymal transition

A Novel Four Mitochondrial Respiration-Related Signature for Predicting Biochemical Recurrence of Prostate Cancer

FTIR microspectroscopy and multivariate analysis facilitate identification of dynamic changes in epithelial‐to‐mesenchymal transition induced by TGF‐β in prostate cancer cells

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