Endothelial surface translocation of mitochondrial PDCE2 involves the non-canonical secretory autophagy pathway: Putative molecular target for radiation-guided drug delivery

Faqihi, Fahimeh; Stoodley, Marcus A.; McRobb, Lucinda S.

doi:10.1016/j.yexcr.2021.112688

Cited by 3 publications

(5 citation statements)

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“…These data show that PDCE2 can be targeted at the cell surface with precision in response to radiation doses of 15 and 25 Gy. The transient peak observed at day two with the higher radiation dose may reflect a rapid peak in non-canonical autophagic processing that is quickly resolved [ 18 ]. Lower radiation doses may stimulate a reduced but prolonged autophagic response, resulting in sustained PDCE2 exposure at the surface.…”

Section: Resultsmentioning

confidence: 99%

“…The immortalized human cerebral microvascular endothelial cell line, hCMEC/D3 (CELLutions Biosystems Inc., Burlington, ON, Canada), was cultured in a complete medium consisting of Endothelial Basal Medium-2 (EBM-2) (Lonza, Basel, Switzerland), fetal bovine serum (5%), penicillin-streptomycin (1%), HEPES (10 mM) (Thermo Fisher, Waltham, MA, USA) and human basic fibroblast growth factor (1 ng/mL) (Sigma-Aldrich, St. Louis, MI, USA), maintained at 37 °C carbon dioxide 5% in humidified 95% air [ 18 ]. All cells between passages 11 and 25 were sub-cultured by trypsin-EDTA solution (Sigma-Aldrich).…”

Section: Methodsmentioning

confidence: 99%

“…However, their frequent exposure in response to other biological stimuli may reduce targeting specificity. Interestingly, canonical autophagic pathways that normally process damaged molecules via the lysosome appear to become overwhelmed after radiation exposure, leading to the non-canonical transport of intracellular proteins to the extracellular space or cell surface [ 18 ]. Functionally, this may represent a survival mechanism for the removal of toxic proteins or a signal (exposure of “self” antigens) to alert the immune system to the presence of stressed or damaged cells [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

“…One such protein is the E2 subunit of pyruvate dehydrogenase (PDCE2). This mitochondrial protein can translocate from intracellular compartments to the endothelial surface in response to high doses of radiation via this unconventional pathway [ 4 , 18 ]. The lack of surface exposure of PDCE2 in healthy tissues may make this an ideal target.…”

Section: Introductionmentioning

confidence: 99%

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Externalization of Mitochondrial PDCE2 on Irradiated Endothelium as a Target for Radiation-Guided Drug Delivery and Precision Thrombosis of Pathological Vasculature

Faqihi

Stoodley

McRobb

2022

IJMS

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Endothelial cells are highly sensitive to ionizing radiation, and exposure leads to multiple adaptive changes. Remarkably, part of this response is the translocation of normally intracellular proteins to the cell surface. It is unclear whether this ectopic expression has a protective or deleterious function, but, regardless, these surface-exposed proteins may provide unique discriminatory targets for radiation-guided drug delivery to vascular malformations or tumor vasculature. We investigated the ability of an antibody–thrombin conjugate targeting mitochondrial PDCE2 (E2 subunit of pyruvate dehydrogenase) to induce precision thrombosis on irradiated endothelial cells in a parallel-plate flow system. Click-chemistry was used to create antibody–thrombin conjugates targeting PDCE2 as the vascular targeting agent (VTA). VTAs were injected into the parallel-plate flow system with whole human blood circulating over irradiated cells. The efficacy and specificity of fibrin-thrombus formation was assessed relative to non-irradiated controls. The PDCE2-targeting VTA dose-dependently increased thrombus formation: minimal thrombosis was induced in response to 5 Gy radiation; doses of 15 and 25 Gy induced significant thrombosis with equivalent efficacy. Negligible VTA binding or thrombosis was demonstrated in the absence of radiation or with non-targeted thrombin. PDCE2 represents a unique discriminatory target for radiation-guided drug delivery and precision thrombosis in pathological vasculature.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Externalization of Mitochondrial PDCE2 on Irradiated Endothelium as a Target for Radiation-Guided Drug Delivery and Precision Thrombosis of Pathological Vasculature

Faqihi

Stoodley

McRobb

2022

IJMS

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“…In vitro and in vivo experiments suggested that DLAT effectively inhibited the growth and metastasis of renal cancer. Faqihi reported that radiation-induced blockade of autophagic flux stimulated redirection of DLAT to the cell surface via a noncanonical secretory autophagy pathway [68]. Such trafficked membrane proteins could provide a unique pool for therapeutic drug delivery.…”

Section: Discussionmentioning

confidence: 99%

A new thinking: deciphering the aberrance and clinical implication of copper-death signatures in clear cell renal cell carcinoma

et al. 2022

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Rationale Recent research has indicated that cuprotosis, or copper induced cell death, is a novel type of cell death that could be utilized as a new weapon for cancer management. However, the characteristics and implications of such signatures in cancers, especially in clear cell renal cell cancer (ccRCC), remain elusive. Methods Expression, methylation, mutation, clinical information, copy number variation, functional implication, and drug sensitivity data at the pan-cancer level were collected from The Cancer Genome Atlas. An unsupervised clustering algorithm was applied to decipher ccRCC heterogeneity. Immune microenvironment construction, immune therapy response, metabolic pattern, and cancer progression signature between subgroups were also investigated. Results Cuprotosis related genes were specifically downregulated in various cancer tissues compared with normal tissues and were correlated with hypermethylation and copy number variation. Cuprotosis scores were also dysregulated in tumor tissues, and we found that such a signature could positively regulate oxidative phosphorylation and Myc and negatively regulate epithelial mesenchymal translation and myogenesis pathways. CPCS1 (cuprotosis scores high) and CPCS2 (cuprotosis scores low) in ccRCC displayed distinctive clinical profiles and biological characteristics; the CPCS2 subtype had a higher clinical stage and a worse prognosis and might positively regulate cornification and epidermal cell differentiation to fuel cancer progression. CPCS2 also displayed a higher tumor mutation burden and low tumor stemness index, while it led to a low ICI therapy response and dysfunctional tumor immunity state. The genome-copy numbers of CPCS2, including arm- gain and arm- loss, were higher than those of CPCS1. The prognostic model constructed based on subgroup biomarkers exerted satisfactory performance in both the training and validation cohorts. In addition, overexpression of the copper death activator DLAT suppressed the malignant ability, including cell migration and proliferation, of renal cell lines in vitro and in vivo. Finally, activation of cuprotosis in tumors could enhance antitumor immunity through dsDNA-cGAS-STING signaling in ccRCC. Conclusion The activation of cuprotosis might function as a promising approach among multiple cancers. The cuprotosis related signatures could reshape tumor immunity in the ccRCC microenvironment via cGAS-STING signal, thus activating tumor antigen-presenting process. Upregulation of DLAT expression in ccRCC cell lines could reactivate the copper death pattern and be treated as a suitable target for ccRCC.

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Autophagy-Dependent Secretion: Crosstalk between Autophagy and Exosome Biogenesis

Zubkova,

Kalinin,

Bolotskaya

et al. 2024

CIMB

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The cellular secretome is pivotal in mediating intercellular communication and coordinating responses to stressors. Exosomes, initially recognized for their role in waste disposal, have now emerged as key intercellular messengers with significant therapeutic and diagnostic potential. Similarly, autophagy has transcended its traditional role as a waste removal mechanism, emerging as a regulator of intracellular communication pathways and a contributor to a unique autophagy-dependent secretome. Secretory authophagy, initiated by various stress stimuli, prompts the selective release of proteins implicated in inflammation, including leaderless proteins that bypass the conventional endoplasmic reticulum–Golgi secretory pathway. This reflects the significant impact of stress-induced autophagy on cellular secretion profiles, including the modulation of exosome release. The convergence of exosome biogenesis and autophagy is exemplified by the formation of amphisomes, vesicles that integrate autophagic and endosomal pathways, indicating their synergistic interplay. Regulatory proteins common to both pathways, particularly mTORC1, emerge as potential therapeutic targets to alter cellular secretion profiles involved in various diseases. This review explores the dynamic interplay between autophagy and exosome formation, highlighting the potential to influence the secretome composition. While the modulation of exosome secretion and cytokine preconditioning is well-established in regenerative medicine, the strategic manipulation of autophagy is still underexplored, presenting a promising but uncharted therapeutic landscape.

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Endothelial surface translocation of mitochondrial PDCE2 involves the non-canonical secretory autophagy pathway: Putative molecular target for radiation-guided drug delivery

Cited by 3 publications

References 38 publications

Externalization of Mitochondrial PDCE2 on Irradiated Endothelium as a Target for Radiation-Guided Drug Delivery and Precision Thrombosis of Pathological Vasculature

Externalization of Mitochondrial PDCE2 on Irradiated Endothelium as a Target for Radiation-Guided Drug Delivery and Precision Thrombosis of Pathological Vasculature

A new thinking: deciphering the aberrance and clinical implication of copper-death signatures in clear cell renal cell carcinoma

Autophagy-Dependent Secretion: Crosstalk between Autophagy and Exosome Biogenesis

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