Peroxisome Metabolism in Cancer

Kim, Jung Ae

doi:10.3390/cells9071692

Cited by 74 publications

(51 citation statements)

References 120 publications

(189 reference statements)

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“…Beyond its recognized role in metabolism and redox homeostasis, the peroxisome is now increasingly regarded as a signaling platform and a key organelle in cellular metabolic reprogramming with major consequences on the immune response, cell cycle, and cell differentiation [ 12 , 96 ]. Elegantly presented in the state of the art of Hlaváč and Souček, several studies have revealed a significant association between the level of expression of peroxisomal ABC transporters and various cancers [ 97 ].…”

Section: Human Diseasesmentioning

confidence: 99%

Peroxisomal ABC Transporters: An Update

Tawbeh

Gondcaille

Trompier

et al. 2021

IJMS

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ATP-binding cassette (ABC) transporters constitute one of the largest superfamilies of conserved proteins from bacteria to mammals. In humans, three members of this family are expressed in the peroxisomal membrane and belong to the subfamily D: ABCD1 (ALDP), ABCD2 (ALDRP), and ABCD3 (PMP70). These half-transporters must dimerize to form a functional transporter, but they are thought to exist primarily as tetramers. They possess overlapping but specific substrate specificity, allowing the transport of various lipids into the peroxisomal matrix. The defects of ABCD1 and ABCD3 are responsible for two genetic disorders called X-linked adrenoleukodystrophy and congenital bile acid synthesis defect 5, respectively. In addition to their role in peroxisome metabolism, it has recently been proposed that peroxisomal ABC transporters participate in cell signaling and cell control, particularly in cancer. This review presents an overview of the knowledge on the structure, function, and mechanisms involving these proteins and their link to pathologies. We summarize the different in vitro and in vivo models existing across the species to study peroxisomal ABC transporters and the consequences of their defects. Finally, an overview of the known and possible interactome involving these proteins, which reveal putative and unexpected new functions, is shown and discussed.

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Section: Human Diseasesmentioning

confidence: 99%

Peroxisomal ABC Transporters: An Update

Tawbeh

Gondcaille

Trompier

et al. 2021

IJMS

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“…However, the suppression of KHK is not dependent on HIF-2α-induced pexophagy, as recuse of the pexophagy by autophagy inhibition does not restore the expression of KHK [ 72 ]. Recent evidence has revealed that the levels of peroxisome proteins or enzymatic activities are either increased or reduced in various cancer types, suggesting that peroxisomes may have a tumor-promoting or tumor-suppressing function [ 73 , 74 ]. Understanding the mechanisms of pexophagy in the control of peroxisome homeostasis is of great importance to decipher the role of peroxisomes in carcinogenesis.…”

Section: Roles Of Pexophagy In Health and Diseasementioning

confidence: 99%

Mechanisms and Functions of Pexophagy in Mammalian Cells

Wang

2021

Cells

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Peroxisomes play essential roles in diverse cellular metabolism functions, and their dynamic homeostasis is maintained through the coordination of peroxisome biogenesis and turnover. Pexophagy, selective autophagic degradation of peroxisomes, is a major mechanism for removing damaged and/or superfluous peroxisomes. Dysregulation of pexophagy impairs the physiological functions of peroxisomes and contributes to the progression of many human diseases. However, the mechanisms and functions of pexophagy in mammalian cells remain largely unknown compared to those in yeast. This review focuses on mammalian pexophagy and aims to advance the understanding of the roles of pexophagy in human health and diseases. Increasing evidence shows that ubiquitination can serve as a signal for pexophagy, and ubiquitin-binding receptors, substrates, and E3 ligases/deubiquitinases involved in pexophagy have been described. Alternatively, pexophagy can be achieved in a ubiquitin-independent manner. We discuss the mechanisms of these ubiquitin-dependent and ubiquitin-independent pexophagy pathways and summarize several inducible conditions currently used to study pexophagy. We highlight several roles of pexophagy in human health and how its dysregulation may contribute to diseases.

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“…Interestingly, GLUT2 mRNA expression is increased following UGCG OE in NMuLi cells. It has been shown that GLUT2 (Tenen et al, 2021) and Acox1 (reviewed in (Kim, 2020)) are increased in HCC, which led us to hypothesize that this might be either a compensatory effect or an early-onset of pro-cancerous processes. PGC1α has an essential role in the control of hepatic gluconeogenesis (reviewed in (Liang and Ward, 2006)), which indicates that PGC1α is upregulated to allow for su cient energy supply for NMuLi/UGCG OE cells, which exhibit decreased OXPHOS and glycolysis.…”

Section: Expression Of Tumor Markers Affected By Ugcgmentioning

confidence: 99%

Increased glucosylceramide production leads to decreased cell energy metabolism and lowered tumor marker expression in non-cancerous liver cells

Wegner

Schömel

Olzomer³

et al. 2021

Preprint

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Hepatocellular carcinoma (HCC) is one of the most difficult cancer types to treat. Liver cancer is often diagnosed at late stages and therapeutic treatment is frequently accompanied by development of multidrug resistance. This leads to poor outcomes for cancer patients. Understanding the fundamental molecular mechanisms leading to liver cancer development is crucial for developing new therapeutic approaches, which are more efficient in treating cancer. Mice with a liver specific UDP-glucose ceramide glucosyltransferase (UGCG) knockout (KO) show delayed diethylnitrosamine (DEN)-induced liver tumor growth. Accordingly, the rationale for our study was to determine whether UGCG overexpression is sufficient to drive cancer phenotypes in liver cells. We investigated the effect of UGCG overexpression (OE) on normal murine liver (NMuLi) cells. Increased UGCG expression results in decreased mitochondrial respiration and glycolysis, which is reversible by treatment with EtDO-P4, an UGCG inhibitor. Furthermore, tumor markers such as FGF21 and EPCAM are lowered following UGCG OE, which could be related to glucosylceramide (GlcCer) and lactosylceramide (LacCer) accumulation in glycosphingolipid-enriched microdomains (GEMs) and subsequently altered signaling protein phosphorylation. These cellular processes lead to decreased proliferation in NMuLi/UGCG OE cells. Our data show that increased UGCG expression itself does not induce pro-cancerous processes in normal liver cells, which indicates that increased GlcCer expression leads to different outcomes in different cancer types.

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Peroxisome Metabolism in Cancer

Cited by 74 publications

References 120 publications

Peroxisomal ABC Transporters: An Update

Peroxisomal ABC Transporters: An Update

Mechanisms and Functions of Pexophagy in Mammalian Cells

Increased glucosylceramide production leads to decreased cell energy metabolism and lowered tumor marker expression in non-cancerous liver cells

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