1-O-Hexadecyl-2-O-methyl-3-O-(2'-acetamido-2'-deoxy-∃-D-glucopyranosyl)-sn-glycerol (Gln) induces cell death with more autophagosomes which is autophagy-independent

Jahreiss, Luca; Renna, Maurizio; Bittman, Robert; Arthur, Gilbert; Rubinsztein, David C.

doi:10.4161/auto.9120

Cited by 25 publications

(33 citation statements)

References 25 publications

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“…It is becoming increasingly clear that, whereas GFP-LC3 and other early autophagy markers are useful for monitoring autophagosome formation, additional assays are required to monitor the flux of substrates through the autophagy pathway. It has already been reported by us and other researchers that a large number of compounds, despite increasing the steady-state levels of GFP-LC3-II, fail to increase the degradation of proteins by autophagy (Zhang et al, 2007;Jahreiss et al, 2009). An increase in levels of LC3-II can have two possible causes: either increased…”

Section: Discussionmentioning

confidence: 99%

“…As previously reported (Jahreiss et al, 2008;Jahreiss et al, 2009), coverslips were blinded and 20 cells per condition were imaged on a Zeiss Axiovert 200M microscope with a LSM 510 confocal attachment using an 63ϫ 1.4 NA Plan Apochromat oilimmersion lens. Laser lines were at 488 nm (lgp120-GFP, RFP-GFP/LC3), 543 nm (mCherry-LC3, RFP-GFP/LC3).…”

Section: Mcherry-lc3 and Gfp-lgp120 Colocalisation Analysismentioning

confidence: 99%

“…To discriminate between these two possibilities, cells were co-transfected with mCherry-LC3 (mCherry is a red fluorescent protein) (Jahreiss et al, 2008;Jahreiss et al, 2009) and GFP-lgp120, the rat homologue of LAMP-1, a commonly used lysosomal marker, which is mainly localised to the limiting membranes of lysosomes and late endosomes (Fukuda, 1991). Compared with control cells, knockdown of Sec22B increased the number of double-positive vesicles, i.e.…”

Section: Sec22b Knockdown Impairs Clearance Of Autophagic Substratesmentioning

confidence: 99%

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Autophagic substrate clearance requires activity of the syntaxin-5 SNARE complex

Renna

Schaffner

Winslow

et al. 2011

Journal of Cell Science

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100

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SummaryAutophagy is a lysosome-dependent cellular catabolic mechanism that mediates the turnover of intracellular organelles and long-lived proteins. Reduced autophagic activity has been shown to lead to the accumulation of misfolded proteins in neurons and might be involved in chronic neurodegenerative diseases. Here, we uncover an essential role for the syntaxin-5 SNARE complex in autophagy. Using genetic knockdown, we show that the syntaxin-5 SNARE complex regulates the later stages of autophagy after the initial formation of autophagosomes. This SNARE complex acts on autophagy by regulating ER-to-Golgi transport through the secretory pathway, which is essential for the activity of lysosomal proteases such as cathepsins. Depletion of syntaxin-5 complex components results in the accumulation of autophagosomes as a result of lysosomal dysfunction, leading to decreased degradation of autophagic substrates. Our findings provide a novel link between a fundamental process such as intracellular trafficking and human diseases that might be affected by defective biogenesis and/or homeostasis of the autophagosome-lysosome degradation system.

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Section: Discussionmentioning

confidence: 99%

Section: Mcherry-lc3 and Gfp-lgp120 Colocalisation Analysismentioning

confidence: 99%

Section: Sec22b Knockdown Impairs Clearance Of Autophagic Substratesmentioning

confidence: 99%

See 1 more Smart Citation

Autophagic substrate clearance requires activity of the syntaxin-5 SNARE complex

Renna

Schaffner

Winslow

et al. 2011

Journal of Cell Science

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100

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“…39 Mechanistic studies demonstrated that GAELs kill cells via an apoptosis-independent mechanism which may involve perturbation of the endocytic pathway and release of cathepsins to mediate cell death independent of apoptosis. 34,40,41 Despite the initial development of GAELs being staggered and non-systematic, the identification of glucosamine-derived non-phosphorus analog 1 and their recent demonstration of cytotoxicity against breast cancer stem cells, 42 have provided the needed impetus to unravel the pharmacophore responsible for their cytotoxicity. …”

Section: Glycosylated Antitumor Ether Lipidsmentioning

confidence: 99%

Design, synthesis and antitumor properties of glycosylated antitumor ether lipid (GAEL)- chlorambucil-hybrids

Idowu

Samadder

Arthur

et al. 2016

Chemistry and Physics of Lipids

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The development of resistance to apoptotic pathways by cancer cells is one of the great impediments to the successful use of chemotherapeutic agents. The development of resistance may be attributed to the role of cancer stem cells in the progression of this disease. One approach to combat drug resistance involves the use of drug combinations that impact multiple targets simultaneously. Although this is believed to be better at controlling complex disease systems, it has often proven to be of limited benefits in terms of overall therapeutic outcomes in cancer treatment. Glycosylated antitumor ether lipids (GAELs) are an emerging class of novel anticancer molecules that is being investigated as potential anticancer drugs. Interest in this class of drug is based on their ability to kill cancer stem cells as well as their non-apoptotic mechanism of action. This provides new opportunities to manipulate cell death in a therapeutic context, especially the renewed ability to kill apoptosis-resistant cancer cells. We therefore hypothesized that hybrid molecules that combine apoptosis-dependent and apoptosis-independent mode of actions in a single molecule may lead to better therapeutic outcomes. We also posited that the amphiphilic nature of GAELs could be modulated and fine-tuned to give a more potent analog.This dissertation describes the antitumor activities of different analogs of GAELchlorambucil hybrids and different triamino analogs. In all, eleven GAEL analogs were synthesized. Their activities, as well as that of reference compounds, were assessed against breast (JIMT1, MDA-MB-231, BT474), pancreas (MiaPaCa2) and prostate (DU145, PC3) cancer cell lines using the MTS assay. Our results reveal that the hybrid concept is a potential viable avenue to pursue as a therapeutic option especially when the other domain is carefully selected (Chapter 3). Moreover, the evidently more potent triamino analog not only corroborate the plausibility of a hybrid drug, it also revealed an important detail about the amphiphilic-cytotoxic relationships of GAELs (Chapter 4). iv ACKNOWLEDGEMENTSMy heartfelt appreciation goes to my indefatigable supervisor, Dr. Frank Schweizer, for his unquantifiable support and understanding, and also for guiding my feet through the 'wilderness' of organic synthesis. His astuteness, inquisitiveness, resourcefulness and right amount of scientific skepticism have rightly shaped me in the pursuit of excellence. He is ever ready and willing to help whenever I run into troubled waters.Also to my co-supervisor, my committee member and our long-standing collaborator, Dr.Gilbert Arthur: his calmness, dexterity, and keen attention to details are unparalleled and 'contagious'. The invaluable contributions of Dr. Pranati Samadder to the success of this work are also deeply appreciated.Many thanks to members of my examining committee: Drs. Jorg Stetefeld, Rebecca Davis and Gilbert Arthur, for your patience, constructive feedbacks and quick response whenever I beckon on you. It was a delight having you all ...

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“…Azithromycin treatment retarded the basal and rapamycin-enhanced degradation of A53T α-synuclein and led to enhanced accumulation of intracellular aggregates of Q74 huntingtin ( Figure 2, A and B). We next examined whether inhibition of LC3-II clearance by azithromycin was caused by failure of autophagosome-lysosome fusion, as seen with long-term treatment with BafA 1 treatment (11), or failure of lysosomal function, a mechanism we recently reported (19). Confocal microscopy of HeLa cells coexpressing mCherry-LC3 and the lysosomal marker lgp120 revealed that although the number of LC3 + vesicles per cell increased with rapamycin, BafA 1 , or azithromycin treatment, the degree of LC3 colocalization with lgp120 was not significantly affected by azithromycin, but was, as expected, enhanced by rapamycin and inhibited by BafA 1 ( Figure 3A).…”

Section: Introductionmentioning

confidence: 99%

Azithromycin blocks autophagy and may predispose cystic fibrosis patients to mycobacterial infection

Renna

Schaffner²,

Brown³

et al. 2011

J. Clin. Invest.

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294

264

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1-O-Hexadecyl-2-O-methyl-3-O-(2'-acetamido-2'-deoxy-∃-D-glucopyranosyl)-sn-glycerol (Gln) induces cell death with more autophagosomes which is autophagy-independent

Cited by 25 publications

References 25 publications

Autophagic substrate clearance requires activity of the syntaxin-5 SNARE complex

Autophagic substrate clearance requires activity of the syntaxin-5 SNARE complex

Design, synthesis and antitumor properties of glycosylated antitumor ether lipid (GAEL)- chlorambucil-hybrids

Azithromycin blocks autophagy and may predispose cystic fibrosis patients to mycobacterial infection

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