UDP-glucose ceramide glucosyltransferase activates AKT, promoted proliferation, and doxorubicin resistance in breast cancer cells

Abstract

The UDP-glucose ceramide glucosyltransferase (UGCG) is a key enzyme in the synthesis of glycosylated sphingolipids, since this enzyme generates the precursor for all complex glycosphingolipids (GSL), the GlcCer. The UGCG has been associated with several cancer-related processes such as maintaining cancer stem cell properties or multidrug resistance induction. The precise mechanisms underlying these processes are unknown. Here, we investigated the molecular mechanisms occurring after UGCG overexpression in breast cancer cells. We observed alterations of several cellular properties such as morphological changes, which enhanced proliferation and doxorubicin resistance in UGCG overexpressing MCF-7 cells. These cellular effects seem to be mediated by an altered composition of glycosphingolipid-enriched microdomains (GEMs), especially an accumulation of globotriaosylceramide (Gb3) and glucosylceramide (GlcCer), which leads to an activation of Akt and ERK1/2. The induction of the Akt and ERK1/2 signaling pathway results in an increased gene expression of multidrug resistance protein 1 (MDR1) and anti-apoptotic genes and a decrease of pro-apoptotic gene expression. Inhibition of the protein kinase C (PKC) and phosphoinositide 3 kinase (PI3K) reduced MDR1 gene expression. This study discloses how changes in UGCG expression impact several cellular signaling pathways in breast cancer cells resulting in enhanced proliferation and multidrug resistance.

Southern Chinese populations harbour non-nucleatum Fusobacteria possessing homologues of the colorectal cancer-associated FadA virulence factor

“… 6 7 61 We annotated the fusobacterial MAGs and observed that while they did not contain key genes involved in TMA production (TMA-lyase ( cutC , K20038), and L-carnitine/gamma-butyrobetaine antiporter ( caiT , K05245)), several orthologues such as proline iminopeptidase (K01259), glutamate formiminotransferase (K00603) and tryptophanase (K01667) were prevalent in genomes from the Fusobacterium clade ( online supplementary table S12 ). Moreover, Fusobacterium clade genomes possess genes that may be involved in the catabolism of amino acids and production of glucose (phosphoenolpyruvate carboxykinase K01610, fructose-bisphosphate aldolase K01623, oxaloacetate decarboxylase K01571), as well as several other features that could be linked to cancer such as iron scavenging (K07230, K07243, K11707, K11708, K11709, K11710), 62 ceramide glucosyltransferase (K00720) involved in production of glycosylated sphingolipids 63 and para-aminobenzoate synthetase (K01664, K01665) in the production of folate. 64 Likewise, urease (K01428–K01430) 65 was detected in Fusobacterium_A and Fusobacterium_B clades but not Fusobacterium .…”

Study on the differentially expressed genes and signaling pathways in dermatomyositis using integrated bioinformatics method

“…UDP-glu-cose ceramide glucosyltransferase (UGCG) can reduce ceramide levels in vivo and induce cells to escape ceramide-induced apoptosis. [ 48 ] UGCG gene can regulate apoptosis-related pathways. Increased expression of UGCG can induce increased expression of anti-apoptotic gene Bcl-2, decreased expression of Bax and Caspase-3.…”

The Glyco-enzyme adaptor GOLPH3 Links Intra-Golgi Transport Dynamics to Glycosylation Patterns and Cell Proliferation

“…In our cell models, the globo pathway is prevalent; and we indeed find that GOLPH3 induces growth through effects on the globo series GSLs. Although the precise mechanism by which they exert their effects remains to be determined, Gb3 and the downstream metabolites Gb4, and sialo-Gb5 have been shown to cluster in GSL rich domains at focal adhesions (Steelant et al, 2002), where they bind to and activate integrins and RTK receptors to promote PI3K-Akt-mTOR signaling (Chuang et al, 2019;Furukawa et al, 2019;Hakomori Si, 2002;Park et al, 2012;Steelant et al, 2002;Wegner et al, 2018). An additional contributing factor to the pro-growth effects of GOLPH3 that is independent of GSL pathway being affected, is the decrease of Cer, a characterized tumor suppressor and inhibitor of cell proliferation (Hannun and Obeid, 2008;Reynolds et al, 2004).…”