scholarly journals Crosstalk between autophagy inhibitors and endosome-related secretory pathways: a challenge for autophagy-based treatment of solid cancers

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Martina Raudenska ◽  
Jan Balvan ◽  
Michal Masarik
Keyword(s):  
Cancer Progression ◽  
Protein Trafficking ◽  
Secretory Pathway ◽  
Clinical Results ◽  
Multivesicular Bodies ◽  
Cancer Type ◽  
Secretory Pathways ◽  
Specific Effects ◽  
Antineoplastic Treatment ◽  
Autophagy Inhibition

AbstractAutophagy is best known for its role in organelle and protein turnover, cell quality control, and metabolism. The autophagic machinery has, however, also adapted to enable protein trafficking and unconventional secretory pathways so that organelles (such as autophagosomes and multivesicular bodies) delivering cargo to lysosomes for degradation can change their mission from fusion with lysosomes to fusion with the plasma membrane, followed by secretion of the cargo from the cell. Some factors with key signalling functions do not enter the conventional secretory pathway but can be secreted in an autophagy-mediated manner.Positive clinical results of some autophagy inhibitors are encouraging. Nevertheless, it is becoming clear that autophagy inhibition, even within the same cancer type, can affect cancer progression differently. Even next-generation inhibitors of autophagy can have significant non-specific effects, such as impacts on endosome-related secretory pathways and secretion of extracellular vesicles (EVs). Many studies suggest that cancer cells release higher amounts of EVs compared to non-malignant cells, which makes the effect of autophagy inhibitors on EVs secretion highly important and attractive for anticancer therapy. In this review article, we discuss how different inhibitors of autophagy may influence the secretion of EVs and summarize the non-specific effects of autophagy inhibitors with a focus on endosome-related secretory pathways. Modulation of autophagy significantly impacts not only the quantity of EVs but also their content, which can have a deep impact on the resulting pro-tumourigenic or anticancer effect of autophagy inhibitors used in the antineoplastic treatment of solid cancers.

scholarly journals Ykt6 membrane-to-cytosol cycling regulates exosomal Wnt secretion

2018 ◽  
Author(s):  
Karen Linnemannstöns ◽  
Pradhipa Karuna M ◽  
Leonie Witte ◽  
Jeanette Clarissa Kittel ◽  
Adi Danieli ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Wnt Signaling ◽  
Signaling Pathways ◽  
Long Range ◽  
Protein Trafficking ◽  
Secretory Pathway ◽  
Multivesicular Bodies ◽  
Phosphorylation Sites ◽  
Wnt Proteins ◽  
C Terminus

Protein trafficking in the secretory pathway, for example the secretion of Wnt proteins, requires tight regulation. These ligands activate Wnt signaling pathways and are crucially involved in development and disease. Wnt is transported to the plasma membrane by its cargo receptor Evi, where Wnt/Evi complexes are endocytosed and sorted onto exosomes for long-range secretion. However, the trafficking steps within the endosomal compartment are not fully understood. The promiscuous SNARE Ykt6 folds into an auto-inhibiting conformation in the cytosol, but a portion associates with membranes by its farnesylated and palmitoylated C-terminus. Here, we demonstrate that membrane detachment of Ykt6 is essential for exosomal Wnt secretion. We identified conserved phosphorylation sites within the SNARE domain of Ykt6, which block Ykt6 cycling from the membrane to the cytosol. In Drosophila, Ykt6-RNAi mediated block of Wg secretion is rescued by wildtype but not phosphomimicking Ykt6. The latter accumulates at membranes, while wildtype Ykt6 regulates Wnt trafficking between the plasma membrane and multivesicular bodies. Taken together, we show that a regulatory switch in Ykt6 fine-tunes sorting of Wnts in endosomes.

scholarly journals Detection of Prostate Cancer via IR Spectroscopic Analysis of Urinary Extracellular Vesicles: A Pilot Study

Membranes ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 591
Author(s):  
Xin-Le Yap ◽  
Bayden Wood ◽  
Teng-Aik Ong ◽  
Jasmine Lim ◽  
Bey-Hing Goh ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Extracellular Vesicles ◽  
Cancer Progression ◽  
Prostate Cancer Screening ◽  
Principal Component ◽  
Urine Samples ◽  
Cancer Type ◽  
Marker Proteins ◽  
Novel Strategy ◽  
Ir Spectroscopic

Extracellular vesicles (EVs) are membranous nanoparticles naturally released from living cells which can be found in all types of body fluids. Recent studies found that cancer cells secreted EVs containing the unique set of biomolecules, which give rise to a distinctive absorbance spectrum representing its cancer type. In this study, we aimed to detect the medium EVs (200–300 nm) from the urine of prostate cancer patients using Fourier transform infrared (FTIR) spectroscopy and determine their association with cancer progression. EVs extracted from 53 urine samples from patients suspected of prostate cancer were analyzed and their FTIR spectra were preprocessed for analysis. Characterization of morphology, particle size and marker proteins confirmed that EVs were successfully isolated from urine samples. Principal component analysis (PCA) of the EV’s spectra showed the model could discriminate prostate cancer with a sensitivity of 59% and a specificity of 81%. The area under curve (AUC) of FTIR PCA model for prostate cancer detection in the cases with 4–20 ng/mL PSA was 0.7, while the AUC for PSA alone was 0.437, suggesting the analysis of urinary EVs described in this study may offer a novel strategy for the development of a noninvasive additional test for prostate cancer screening.

Regulated and constitutive secretion of distinct molecular forms of acetylcholinesterase from PC12 cells

1993 ◽  
Vol 106 (3) ◽  
pp. 731-740 ◽  
Author(s):  
E.S. Schweitzer
Keyword(s):  
Pc12 Cells ◽  
Secretory Pathway ◽  
Intracellular Localization ◽  
Synaptic Function ◽  
Molecular Forms ◽  
Secretory Proteins ◽  
Secretory Pathways ◽  
Regulated Secretion ◽  
Constitutive Secretion ◽  
A Cell

PC12 cells secrete the enzyme acetylcholinesterase (AChE) while at rest, and increase the overall rate of this secretion 2-fold upon depolarization. This behavior is different from the release of other markers by the constitutive or regulated secretory pathways in PC12 cells. Both the resting and stimulated release of AChE are unchanged after treatment with a membrane-impermeable esterase inhibitor, demonstrating that it represents true secretion and not shedding from the cell surface. The stimulation release of AChE is Ca(2+)-dependent, while the unstimulated release is not. Analysis of the molecular forms of AChE secreted by PC12 cells indicates that the release of AChE actually involves two concurrent but independent secretory processes, and that the G4 form of the enzyme is secreted constitutively, while both the G2 and G4 forms are secreted in a regulated manner, presumably from regulated secretory vesicles. Compared with other regulated secretory proteins, a much smaller fraction of cellular AChE is secreted, and the intracellular localization of this enzyme differs from that of other regulated secretory proteins. The demonstration that a cell line that exhibits regulated secretion of acetylcholine (ACh) is also capable of regulated secretion of AChE provides additional evidence for the existence of multiple regulated secretory pathways within a single cell. Moreover, there appears to be a selective packaging of different molecular forms of AChE into the regulated versus the constitutive secretory pathway. Both the specificity of sorting of AChE and the regulation of its secretion suggest that AChE may play a more dynamic role in synaptic function than has been recognized previously.

scholarly journals The Role of Autophagy in the Progression and Treatment of Tumors

2021 ◽  
Vol 1 ◽  
pp. 62-71
Author(s):  
Ismail Al-Janabi
Keyword(s):  
Clinical Trials ◽  
Cancer Progression ◽  
Cancer Type ◽  
Homeostatic Mechanism ◽  
Context Dependent ◽  
Initiation Stage ◽  
The Relationship

Autophagy is a conserved homeostatic mechanism enabling cells to cope with various stresses. The pathways leading up to the activation of autophagy are interconnected with those of tumorigenesis. However, the relationship between the two events is not a straightforward one and very often context-dependent. Generally, autophagy appears to act against the tumor during the initiation stage and most often drives cancer progression subsequently. Published clinical trials for the treatment of various tumors, where autophagy was pharmacologically inhibited, were obtained and tabulated. Targeting autophagy for the treatment of tumors can be rewarding in the appropriate context, such as cancer type, grade, and microenvironment.

scholarly journals Her2-Targeted Therapy Induces Autophagy in Esophageal Adenocarcinoma Cells

2018 ◽  
Vol 19 (10) ◽  
pp. 3069 ◽  
Author(s):  
Félice Janser ◽  
Olivia Adams ◽  
Vanessa Bütler ◽  
Anna Schläfli ◽  
Bastian Dislich ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Esophageal Adenocarcinoma ◽  
Acquired Resistance ◽  
Therapy Resistance ◽  
Her2 Status ◽  
Autophagic Flux ◽  
Cancer Type ◽  
Cancer Resistance ◽  
Her2 Positive ◽  
Autophagy Inhibition

Esophageal adenocarcinoma (EAC) is a highly lethal cancer type with an overall poor survival rate. Twenty to thirty percent of EAC overexpress the human epidermal growth factor receptor 2 (Her2), a transmembrane receptor tyrosine kinase promoting cell growth and proliferation. Patients with Her2 overexpressing breast and gastroesophageal cancer may benefit from Her2 inhibitors. Therapy resistance, however, is well documented. Since autophagy, a lysosome-dependent catabolic process, is implicated in cancer resistance mechanisms, we tested whether autophagy modulation influences Her2 inhibitor sensitivity in EAC. Her2-positive OE19 EAC cells showed an induction in autophagic flux upon treatment with the small molecule Her2 inhibitor Lapatinib. Newly generated Lapatinib-resistant OE19 (OE19 LR) cells showed increased basal autophagic flux compared to parental OE19 (OE19 P) cells. Based on these results, we tested if combining Lapatinib with autophagy inhibitors might be beneficial. OE19 P showed significantly reduced cell viability upon double treatment, while OE19 LR were already sensitive to autophagy inhibition alone. Additionally, Her2 status and autophagy marker expression (LC3B and p62) were investigated in a treatment-naïve EAC patient cohort (n = 112) using immunohistochemistry. Here, no significant correlation between Her2 status and expression of LC3B and p62 was found. Our data show that resistance to Her2-directed therapy is associated with a higher basal autophagy level, which is not per se associated with Her2 status. Therefore, we propose that autophagy may contribute to acquired resistance to Her2-targeted therapy in EAC, and that combining Her2 and autophagy inhibition might be beneficial for EAC patients.

scholarly journals Molecular mechanism to recruit galectin-3 into multivesicular bodies for polarized exosomal secretion

2018 ◽  
Vol 115 (19) ◽  
pp. E4396-E4405 ◽  
Author(s):  
Sebastian Bänfer ◽  
Dominik Schneider ◽  
Jenny Dewes ◽  
Maximilian T. Strauss ◽  
Sven-A. Freibert ◽  
...  
Keyword(s):  
Secretory Pathway ◽  
Direct Interaction ◽  
Multivesicular Body ◽  
Dominant Negative ◽  
Amino Terminus ◽  
Multivesicular Bodies ◽  
Dramatic Decrease ◽  
Endosomal Sorting ◽  
Galectin 3 ◽  
Binding Lectin

The beta-galactoside binding lectin galectin-3 (Gal3) is found intracellularly and in the extracellular space. Secretion of this lectin is mediated independently of the secretory pathway by a not yet defined nonclassical mechanism. Here, we found Gal3 in the lumen of exosomes. Superresolution and electron microscopy studies visualized Gal3 recruitment and sorting into intraluminal vesicles. Exosomal Gal3 release depends on the endosomal sorting complex required for transport I (ESCRT-I) component Tsg101 and functional Vps4a. Either Tsg101 knockdown or expression of dominant-negative Vps4aE228Q causes an intracellular Gal3 accumulation at multivesicular body formation sites. In addition, we identified a highly conserved tetrapeptide P(S/T)AP motif in the amino terminus of Gal3 that mediates a direct interaction with Tsg101. Mutation of the P(S/T)AP motif results in a loss of interaction and a dramatic decrease in exosomal Gal3 secretion. We conclude that Gal3 is a member of endogenous non-ESCRT proteins which are P(S/T)AP tagged for exosomal release.

scholarly journals Diversity spectrum analysis identifies mutation-specific effects of cancer driver genes

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Xiaobao Dong ◽  
Dandan Huang ◽  
Xianfu Yi ◽  
Shijie Zhang ◽  
Zhao Wang ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Spectrum Analysis ◽  
Driver Mutations ◽  
Driver Gene ◽  
Cancer Type ◽  
Driver Genes ◽  
Drug Responses ◽  
Cancer Driver ◽  
Specific Effects ◽  
Cancer Driver Genes

AbstractMutation-specific effects of cancer driver genes influence drug responses and the success of clinical trials. We reasoned that these effects could unbalance the distribution of each mutation across different cancer types, as a result, the cancer preference can be used to distinguish the effects of the causal mutation. Here, we developed a network-based framework to systematically measure cancer diversity for each driver mutation. We found that half of the driver genes harbor cancer type-specific and pancancer mutations simultaneously, suggesting that the pervasive functional heterogeneity of the mutations from even the same driver gene. We further demonstrated that the specificity of the mutations could influence patient drug responses. Moreover, we observed that diversity was generally increased in advanced tumors. Finally, we scanned potentially novel cancer driver genes based on the diversity spectrum. Diversity spectrum analysis provides a new approach to define driver mutations and optimize off-label clinical trials.

scholarly journals Glycosylphosphatidylinositol-Dependent Protein Trafficking in Bloodstream Stage Trypanosoma brucei

2003 ◽  
Vol 2 (1) ◽  
pp. 76-83 ◽  
Author(s):  
Veronica P. Triggs ◽  
James D. Bangs
Keyword(s):  
Trypanosoma Brucei ◽  
Protein Trafficking ◽  
Secretory Pathway ◽  
Surface Glycoprotein ◽  
Cysteine Protease Inhibitor ◽  
Velocity Sedimentation ◽  
Control Mechanisms ◽  
Er Quality Control ◽  
Lysosomal Protease ◽  
Dependent Transport

ABSTRACT We have previously demonstrated that glycosylphosphatidylinositol (GPI) anchors strongly influence protein trafficking in the procyclic insect stage of Trypanosoma brucei (M. A. McDowell, D. A. Ransom, and J. D. Bangs, Biochem. J. 335:681-689, 1998), where GPI-minus variant surface glycoprotein (VSG) reporters have greatly reduced rates of endoplasmic reticulum (ER) exit but are ultimately secreted. We now demonstrate that GPI-dependent trafficking also occurs in pathogenic bloodstream trypanosomes. However, unlike in procyclic trypanosomes, truncated VSGs lacking C-terminal GPI-addition signals are not secreted but are mistargeted to the lysosome and degraded. Failure to export these reporters is not due to a deficiency in secretion of these cells since the N-terminal ATPase domain of the endogenous ER protein BiP is efficiently secreted from transgenic cell lines. Velocity sedimentation experiments indicate that GPI-minus VSG dimerizes similarly to wild-type VSG, suggesting that degradation is not due to ER quality control mechanisms. However, GPI-minus VSGs are fully protected from degradation by the cysteine protease inhibitor FMK024, a potent inhibitor of the major lysosomal protease trypanopain. Immunofluorescence of cells incubated with FMK024 demonstrates that GPI-minus VSG colocalizes with p67, a lysosomal marker. These data suggest that in the absence of a GPI anchor, VSG is mistargeted to the lysosome and subsequently degraded. Our findings indicate that GPI-dependent transport is a general feature of secretory trafficking in both stages of the life cycle. A working model is proposed in which GPI valence regulates progression in the secretory pathway of bloodstream stage trypanosomes.

Chemotherapy use during the last 30 days of life in patients with cancer.

2012 ◽  
Vol 30 (34_suppl) ◽  
pp. 231-231
Author(s):  
Maria Alma Rodriguez ◽  
Yvette DeJesus ◽  
Lee Cheng
Keyword(s):  
Cancer Progression ◽  
Treatment Options ◽  
Hematologic Malignancies ◽  
Care Plan ◽  
Cancer Center ◽  
Cancer Type ◽  
Time Of Death ◽  
University Of Texas ◽  
Advanced Planning ◽  
Oncology Practice

231 Background: Treatment options are increasingly available to patients with advanced cancer. Appropriately timed cession of chemotherapy is a quality-of-care measure in the Quality Oncology Practice Initiative of the American Society of Clinical Oncology. To gain insight into whether communication about end-of-life (EOL) issues might need to be improved, we analyzed chemotherapy use during the 30 days at the EOL (EOLCx) among patients at large cancer center. We also analyzed the presence of electronic DNR (eDNR) orders at the time of death in hospital as a surrogate indicator of EOL discussions. Methods: We reviewed the records of cancer patients (age≥18 years) who received their care at The University of Texas MD Anderson Cancer Center and died between December 2010 and May 2012. Logistic regression was used to measure associations of EOLCx and age, gender, ethnicity, comorbidities, cancer type, and cancer progression. Results: A total of 7,399 patients met the inclusion criteria. The median age was 64 years; 46% were female and 18% had hematologic malignancies (HM). 996 patients (14%) received EOLCx, and of these, 554 died in the hospital (7%, 554/7,399). Of those who died in the hospital, 93% had eDNR orders (no difference between solid tumors [ST] and HM). The EOLCx was higher for patients who died in the hospital than for those who died elsewhere (44% vs 7%) and higher for patients with HM than for those with ST (38% vs 8%). EOLCx was more common in patients with ST with metastases, HM without relapse, and HM with relapse than in those with ST without metastases [odds ratios (ORs), 3.3, 13.9, and 32.8, respectively; all p<0.05]. EOLCx was less common in older patients (≥65 years) than younger patients (OR, 0.6; p<0.05) and was more common in patients with comorbidities than in those without (OR, 1.3; p<0.05) and in patients who were not black or Hispanic than in white patients (OR, 1.6; p<0.05). No difference of EOLCx between genders was found. Conclusions: EOLCx was more common in patients with HM with or without relapse than in patients with ST. Most patients had eDNR orders at the time of death in hospital. The results suggest that communication about prognosis and advanced planning about the goals of medical care is becoming critical part in overall oncologic care plan.

scholarly journals Subviral Hepatitis B Virus Filaments, like Infectious Viral Particles, Are Released via Multivesicular Bodies

2015 ◽  
Vol 90 (7) ◽  
pp. 3330-3341 ◽  
Author(s):  
Bingfu Jiang ◽  
Kiyoshi Himmelsbach ◽  
Huimei Ren ◽  
Klaus Boller ◽  
Eberhard Hildt
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Secretory Pathway ◽  
Current Model ◽  
Surface Protein ◽  
Surface Proteins ◽  
Multivesicular Bodies ◽  
Viral Particles ◽  
B Virus ◽  
Subviral Particles

ABSTRACTIn addition to infectious viral particles, hepatitis B virus-replicating cells secrete large amounts of subviral particles assembled by the surface proteins, but lacking any capsid and genome. Subviral particles form spheres (22-nm particles) and filaments. Filaments contain a much larger amount of the large surface protein (LHBs) compared to spheres. Spheres are released via the constitutive secretory pathway, while viral particles are ESCRT-dependently released via multivesicular bodies (MVBs). The interaction of virions with the ESCRT machinery is mediated by α-taxilin that connects the viral surface protein LHBs with the ESCRT component tsg101. Since filaments in contrast to spheres contain a significant amount of LHBs, it is unclear whether filaments are released like spheres or like virions. To study the release of subviral particles in the absence of virion formation, a core-deficient HBV mutant was generated. Confocal microscopy, immune electron microscopy of ultrathin sections and isolation of MVBs revealed that filaments enter MVBs. Inhibition of MVB biogenesis by the small-molecule inhibitor U18666A or inhibition of ESCRT functionality by coexpression of transdominant negative mutants (Vps4A, Vps4B, and CHMP3) abolishes the release of filaments while the secretion of spheres is not affected. These data indicate that in contrast to spheres which are secreted via the secretory pathway, filaments are released via ESCRT/MVB pathway like infectious viral particles.IMPORTANCEThis study revises the current model describing the release of subviral particles by showing that in contrast to spheres, which are secreted via the secretory pathway, filaments are released via the ESCRT/MVB pathway like infectious viral particles. These data significantly contribute to a better understanding of the viral morphogenesis and might be helpful for the design of novel antiviral strategies.

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