Spermine synthesis inhibitor blocks 25-hydroxycholesterol-induced- apoptosis via SREBP2 upregulation in DLD-1 cell spheroids

Kakimoto, Miku; Yamamoto, Hideya; Tanaka, Akihiro

doi:10.1016/j.bbrep.2020.100754

Cited by 7 publications

(6 citation statements)

References 30 publications

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“…Cell culture HT29/WiDr (Japanese Collection of Research Bioresources [JCRB], Osaka, Japan) and DLD1 (JCRB) cell lines were grown in RPMI 1680 medium (Fuji lm Wako Pure Chemical Corporation, Osaka, Japan) supplemented with 10% fetal bovine serum (FBS; Nichirei, Tokyo, Japan) and penicillin/streptomycin (Fuji lm Wako) at 37℃ in a CO 2 incubator. For spheroid formation, round-bottom 96-well plates were coated with poly-(2-hydroxyethyl methacrylate (poly-HEMA; Sigma Aldrich, St Louis, MI, USA) (Kakimoto et al 2020). Cell spheroids were observed with an inverted light microscope (CKX-41; Olympus, Tokyo, Japan) and photographed using a DP25 digital camera (Olympus).…”

Section: Methodsmentioning

confidence: 99%

Physiological Methylmalonic Acid Contributes to Cell Growth via Mitochondrial Dysfunction in Colorectal Cancer Cell Spheroids

Tanaka,

Murakami,

Yamamoto

2023

Preprint

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Methylmalonic acid (MMA) is a small molecule produced during the metabolism of branched-chain amino acids. Recently, it was reported that the blood concentration of MMA increased with age and that it also promoted lung cancer metastasis. However, little is known about how it affects cancers other than lung cancer. In this study, we examined the influences of MMA on colorectal cancer cell spheroids. We found that MMA promoted proliferation of colorectal cancer spheroids in a glutamine-dependent manner at physiological concentrations; MMA induced mitochondrial reactive oxygen species generation, which in turn affected the promotion of cell growth. Methylmalonic acid treatment also induced a metabolic shift to the glycolytic system. These results suggest that physiological concentrations of MMA may promote cancer cell proliferation by decreasing mitochondrial function and inducing a metabolic shift, and add new insights into the effect of aging on cancer.

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Section: Methodsmentioning

confidence: 99%

Physiological Methylmalonic Acid Contributes to Cell Growth via Mitochondrial Dysfunction in Colorectal Cancer Cell Spheroids

Tanaka,

Murakami,

Yamamoto

2023

Preprint

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“…Several studies support this view highlighting increased activity of the mevalonate pathway in CSCs of CRC. In the same light, it has been hypothesized that crosstalk exists between polyamine metabolism and the cholesterol synthesis pathways via SREBP2 which govern the proliferative and malignant potential of cells ( 81 ). In DLD-1 spheroids administering spermine (polyamine synthesis inhibitor) APCHA, inhibited 25-hydroxycholesterol (25-HC)-induced apoptosis in a SREBP2 manner.…”

Section: The Utility Of 3d Models In Studying Molecular Mechanisms Of...mentioning

confidence: 99%

“…In DLD-1 spheroids administering spermine (polyamine synthesis inhibitor) APCHA, inhibited 25-hydroxycholesterol (25-HC)-induced apoptosis in a SREBP2 manner. This inhibition resulted in increased transcriptional activity of SREBP2 and reduced apoptosis in DLD-1 spheroids ( 81 ).…”

Section: The Utility Of 3d Models In Studying Molecular Mechanisms Of...mentioning

confidence: 99%

The utility of 3D models to study cholesterol in cancer: Insights and future perspectives

2023

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Cholesterol remains a vital molecule required for life; however, increasing evidence exists implicating cholesterol in cancer development and progression. Numerous studies investigating the relationship between cholesterol and cancer in 2-dimensional (2D) culture settings exist, however these models display inherent limitations highlighting the incipient need to develop better models to study disease pathogenesis. Due to the multifaceted role cholesterol plays in the cell, researchers have begun utilizing 3-dimensional (3D) culture systems, namely, spheroids and organoids to recapitulate cellular architecture and function. This review aims to describe current studies exploring the relationship between cancer and cholesterol in a variety of cancer types using 3D culture systems. We briefly discuss cholesterol dyshomeostasis in cancer and introduce 3D in-vitro culture systems. Following this, we discuss studies performed in cancerous spheroid and organoid models that focused on cholesterol, highlighting the dynamic role cholesterol plays in various cancer types. Finally, we attempt to provide potential gaps in research that should be explored in this rapidly evolving field of study.

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“…It has been reported that spermine facilitate tumor progression through maintaining protein and nucleic acid synthesis, reducing reactive oxygen-induced damage, and regulating multiple ion channels necessary for cell-to-cell communication [10][11][12]. Depletion of polyamines including spermine usually causes growth arrest and apoptosis in cancer cells through the intrinsic mitochondrial pathway, as indicated by the changes in biochemical parameters, such as the loss of mitochondrial membrane potential, changes in the expression of Bcl-2 family proteins, release of cytochrome c and caspase 3 activation [13][14][15].…”

Section: Introductionmentioning

confidence: 99%

Elevation of spermine remodels immunosuppressive microenvironment through driving the modification of PD-L1 in hepatocellular carcinoma

et al. 2022

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Background Spermine is frequently elevated in tumor tissues and body fluids of cancer patients and is critical for cancer cell proliferation, migration and invasion. However, the immune functions of spermine in hepatocellular carcinoma progression remains unknown. In the present study, we aimed to elucidate immunosuppressive role of spermine in hepatocellular carcinoma and to explore the underlying mechanism. Methods Whole-blood spermine concentration was measured using HPLC. Human primary HCC tissues were collected to examine the expression of CaSR, p-Akt, β-catenin, STT3A, PD-L1, and CD8. Mouse model of tumorigenesis and lung metastasis were established to evaluate the effects of spermine on hepatocellular carcinoma. Western blotting, immunofluorescence, real time PCR, digital Ca2+ imaging, and chromatin immunoprecipitation assay were used to investigate the underlying mechanisms by which spermine regulates PD-L1 expression and glycosylation in hepatocellular carcinoma cells. Results Blood spermine concentration in the HCC patient group was significantly higher than that in the normal population group. Spermine could facilitate tumor progression through inducing PD-L1 expression and decreasing the CD8+ T cell infiltration in HCC. Mechanistically, spermine activates calcium-sensing receptor (CaSR) to trigger Ca2+ entry and thereby promote Akt-dependent β-catenin stabilization and nuclear translocation. Nuclear β-catenin induced by spermine then activates transcriptional expression of PD-L1 and N-glycosyltransferase STT3A, while STT3A in turn increases the stability of PD-L1 through inducing PD-L1 protein N-glycosylation in HCC cells. Conclusions This study reveals the crucial function of spermine in establishing immune privilege by increasing the expression and N-glycosylation of PD-L1, providing a potential strategy for the treatment of hepatocellular carcinoma.

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Spermine synthesis inhibitor blocks 25-hydroxycholesterol-induced- apoptosis via SREBP2 upregulation in DLD-1 cell spheroids

Cited by 7 publications

References 30 publications

Physiological Methylmalonic Acid Contributes to Cell Growth via Mitochondrial Dysfunction in Colorectal Cancer Cell Spheroids

Physiological Methylmalonic Acid Contributes to Cell Growth via Mitochondrial Dysfunction in Colorectal Cancer Cell Spheroids

The utility of 3D models to study cholesterol in cancer: Insights and future perspectives

Elevation of spermine remodels immunosuppressive microenvironment through driving the modification of PD-L1 in hepatocellular carcinoma

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