Upregulation of human glycolipid transfer protein (GLTP) induces necroptosis in colon carcinoma cells

Mishra, Shrawan K.; Stephenson, Daniel J.; Chalfant, Charles E.; Brown, Rhoderick E.

doi:10.1016/j.bbalip.2018.11.002

Cited by 22 publications

(20 citation statements)

References 79 publications

(121 reference statements)

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“… 33 Other mechanisms, such as upregulation of glycolipid transfer protein via RIPK3, have also been found to induce necroptosis. 34 Therefore, in the future, it would be useful to investigate whether the necroptotic effect of GDC-0326 is mediated by PI3K/AKT/mTOR or other signaling pathways. Another limitation of GDC-0326 is that it is insoluble in water.…”

Section: Discussionmentioning

confidence: 99%

GDC-0326 Enhances the Effects of 5-Fu in Colorectal Cancer Cells by Inducing Necroptotic Death

Zhang¹,

Ju²,

Chen³

et al. 2021

OTT

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Aim Chemoresistance to 5-fluorouracil (5-Fu) is common in colorectal cancer (CRC). Programmed necrosis (necroptosis) is an alternative form of programmed cell death regulated by receptor-interacting protein kinase (RIPK) 1 and 3, assumed as a novel target of cancer therapy. In this study, we aimed to explore whether a novel small molecular agent GDC-0326 could facilitate the effect of 5-Fu through necroptosis. Main Methods Cell Counting Kit-8 (CCK-8) assay and colony formation were performed to confirm the function of GDC-0326 in CRC cells. Western blot and immunofluorescence were conducted to measure the altered expressions of RIPK1/RIPK3 induced by GDC-0326. Subcutaneous tumor models were used to evaluate the chemotherapeutic effects and concomitant side effects of GDC-0326 in vivo. Key Findings We found that GDC-0326 effectively suppressed the growth of CRC cells in a dose-dependent manner. The induction of necroptosis by GDC-0326 was correlated with the modulation of RIPK1 and RIPK3. Necrostatin-1 and GSK-872, inhibitors of RIPK1 and RIPK3, respectively, could rescue the cell death induced by GDC-0326. In addition, in vitro and in vivo studies showed that 5-Fu plus GDC-0326 evinced a better antitumor efficacy by suppressing tumor growth and increasing tumor necrosis with no increased toxicity. Significance This study demonstrates that GDC-0326 plus 5-Fu has augmented antitumor efficacy and acceptable safety, which might be a promising therapeutic strategy for CRC patients in the future.

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Section: Discussionmentioning

confidence: 99%

GDC-0326 Enhances the Effects of 5-Fu in Colorectal Cancer Cells by Inducing Necroptotic Death

Zhang¹,

Ju²,

Chen³

et al. 2021

OTT

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“…Cer likely flips between the two sides of the ER membrane, possibly assisted by flippase proteins. Cer is then distributed to Golgi membranes, either through vesicular transport or assisted by the cytosolic protein GLTP that mediates non-vesicular intramembrane trafficking of GSLs [54,55]. Further extension of Cer takes place in the Golgi apparatus by membrane-bound GTs and sulfotransferases [56].…”

Section: Biosynthesis Of Glycosphingolipidsmentioning

confidence: 99%

Metabolism of Glycosphingolipids and Their Role in the Pathophysiology of Lysosomal Storage Disorders

Ryckman

Brockhausen

Walia

2020

IJMS

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Glycosphingolipids (GSLs) are a specialized class of membrane lipids composed of a ceramide backbone and a carbohydrate-rich head group. GSLs populate lipid rafts of the cell membrane of eukaryotic cells, and serve important cellular functions including control of cell–cell signaling, signal transduction and cell recognition. Of the hundreds of unique GSL structures, anionic gangliosides are the most heavily implicated in the pathogenesis of lysosomal storage diseases (LSDs) such as Tay-Sachs and Sandhoff disease. Each LSD is characterized by the accumulation of GSLs in the lysosomes of neurons, which negatively interact with other intracellular molecules to culminate in cell death. In this review, we summarize the biosynthesis and degradation pathways of GSLs, discuss how aberrant GSL metabolism contributes to key features of LSD pathophysiology, draw parallels between LSDs and neurodegenerative proteinopathies such as Alzheimer’s and Parkinson’s disease and lastly, discuss possible therapies for patients.

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“…GLTP is known to mediate intermembrane trafficking of glycosphingolipids and regulate their homeostatic levels within cells [56,57]. Mechanistically, upregulation of human GLTP was shown to promote RIPK3-dependent MLKL activation, which increased expression levels of Kip1/p27 and Cip1/p21, and induced Ca 2+ release from internal stores to trigger necroptosis in colon carcinoma cells [58].…”

Section: Glycolipid Transfer Protein (Gltp)mentioning

confidence: 99%

Regulation of Necroptosis by Phospholipids and Sphingolipids

Zhang

Matsuda

Yaegashi

et al. 2020

Cells

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Several non-apoptotic regulated cell death pathways have been recently reported. Necroptosis, a form of necrotic-regulated cell death, is characterized by the involvement of receptor-interacting protein kinases and/or the pore-forming mixed lineage kinase domain-like protein. Recent evidence suggests a key role for lipidic molecules in the regulation of necroptosis. The purpose of this mini-review is to outline the regulation of necroptosis by sphingolipids and phospholipids.

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Upregulation of human glycolipid transfer protein (GLTP) induces necroptosis in colon carcinoma cells

Cited by 22 publications

References 79 publications

GDC-0326 Enhances the Effects of 5-Fu in Colorectal Cancer Cells by Inducing Necroptotic Death

GDC-0326 Enhances the Effects of 5-Fu in Colorectal Cancer Cells by Inducing Necroptotic Death

Metabolism of Glycosphingolipids and Their Role in the Pathophysiology of Lysosomal Storage Disorders

Regulation of Necroptosis by Phospholipids and Sphingolipids

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