Hsp70 in cancer: A double agent in the battle between survival and death

Vostakolaei, Mehdi Asghari; Hatami-Baroogh, Leila; Babaei, Ghader; Molavi, Ommoleila; Kordi, Shirafkan; Abdolalizadeh, Jalal

doi:10.1002/jcp.30132

Cited by 53 publications

(55 citation statements)

References 233 publications

(459 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The ability of HSP to chaperone TAAs and facilitate their uptake by APCs with subsequently endorsed cross-presentation is central to their immunogenic effects. Furthermore, HSPs recruit leukocytes, polarize Th cell responses towards Th1 cells, activate NK cells as well as induce the maturation of DCs (163,203). While reliable evidence that tumor-derived HSP-peptide complexes are able to enhance cross-presentation of TAAs has been brought forward by several studies, the exploration of their immunogenic effects may be warranted to boost in situ vaccination strategies.…”

Section: Hspsmentioning

confidence: 99%

In Situ Vaccination as a Strategy to Modulate the Immune Microenvironment of Hepatocellular Carcinoma

et al. 2021

View full text Add to dashboard Cite

Hepatocellular Carcinoma (HCC) is a highly prevalent malignancy that develops in patients with chronic liver diseases and dysregulated systemic and hepatic immunity. The tumor microenvironment (TME) contains tumor-associated macrophages (TAM), cancer-associated fibroblasts (CAF), regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC) and is central to mediating immune evasion and resistance to therapy. The interplay between these cells types often leads to insufficient antigen presentation, preventing effective anti-tumor immune responses. In situ vaccines harness the tumor as the source of antigens and implement sequential immunomodulation to generate systemic and lasting antitumor immunity. Thus, in situ vaccines hold the promise to induce a switch from an immunosuppressive environment where HCC cells evade antigen presentation and suppress T cell responses towards an immunostimulatory environment enriched for activated cytotoxic cells. Pivotal steps of in situ vaccination include the induction of immunogenic cell death of tumor cells, a recruitment of antigen-presenting cells with a focus on dendritic cells, their loading and maturation and a subsequent cross-priming of CD8+ T cells to ensure cytotoxic activity against tumor cells. Several in situ vaccine approaches have been suggested, with vaccine regimens including oncolytic viruses, Flt3L, GM-CSF and TLR agonists. Moreover, combinations with checkpoint inhibitors have been suggested in HCC and other tumor entities. This review will give an overview of various in situ vaccine strategies for HCC, highlighting the potentials and pitfalls of in situ vaccines to treat liver cancer.

show abstract

Section: Hspsmentioning

confidence: 99%

In Situ Vaccination as a Strategy to Modulate the Immune Microenvironment of Hepatocellular Carcinoma

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Diferentes estudos reportam que as proteínas Hsp70 são imprescindíveis para a viabilidade das células eucarióticas por apresentar funções citoprotetoras e atenuar a formação de agregados proteicos (BRODSKY;CHIOSIS, 2006;DEMYANENKO et al, 2020;FULDA et al, 2010;MACARIO;CONWAY DE MACARIO, 2005;WESTERHEIDE;MORIMOTO, 2005). Além disso, tem sido visto que as Hsp70 podem auxiliar na adaptação e sobrevivência de diferentes tipos celulares por interagir com diferentes fatores de transcrição (incluindo a p53), atuando portanto na regulação celular (HAGEMAN et al, 2011;VOSTAKOLAEI et al, 2020;WALERYCH et al, 2009;ZYLICZ;KING;WAWRZYNOW, 2001). O envolvimento das Hsp70 em doenças neurodegenerativas, tais como Parkinson, Huntington e Alzheimer, também tem sido recorrentemente estudado, sendo que essa família de chaperonas vem sendo proposta como um potencial alvo terapêutico para tais patologias (CIECHANOVER; KWON, 2017;ELLIOTT;TSVETKOV;GINZBURG, 2007;ENOGIERU et al, 2019;LACKIE et al, 2018;NACHMAN et al, 2020;SÕTI et al, 2005;VAN LEEUWEN;WESTERHEIDE;MORIMOTO, 2005).…”

Section: Hsp70unclassified

“…De forma geral, embora compartilhem moderado grau de identidade (Tabela 5) e possuam estruturas secundárias bastante similares (Figura 13A), as proteínas HspA5 e HspA8 apresentam diferenças locais em termos de estrutura terciária (Figura 13B, 14 e 15), o que pode influenciar e resultar nas distintas funções as quais estas chaperonas estão envolvidas (RADONS, 2016;VOSTAKOLAEI et al, 2020).…”

Section: Caracterização Da Estrutura Secundária E Terciáriaunclassified

“…a induzida por estresse; b não induzida por estresse. Fonte: Adaptado de (RADONS, 2016) e(VOSTAKOLAEI et al, 2020).…”

unclassified

“…). A HspA5 é encontrada principalmente no RE (Tabela 2), mas também pode estar presente nas mitocôndrias, no citoplasma, no nucleoplasma, na superfície celular e em exossomos (IBRAHIM; ABDELMALEK;ELFIKY, 2019;SUN et al, 2006;TSAI;LEE, 2018;VOSTAKOLAEI et al, 2020), Assim como a maior parte das Hsp70 homólogas, a HspA5 é constituída pelos dois domínios estruturais canônicos, DLN e DLP (Figura 7). Ela também apresenta um peptídeo sinal de endereçamento ao RE no DLN e uma sequência de retenção KDEL presente no final do DLP (JIN; KOMITA; AOE, 2017).…”

unclassified

See 2 more Smart Citations

Caracterização estrutural, funcional e estabilidade térmica das proteínas humanas HspA5 e HspA8: uma abordagem comparativa

Silva¹

View full text Add to dashboard Cite

Heat shock proteins (Hsps) are important components of cell protein quality control (PQC), acting on protein synthesis, folding, traffic and degradation. The central component in the PQC is the Hsp70 family, which consists of highly conserved, ubiquitous and ATP-dependent molecular chaperones. These chaperones can assume different conformations that are regulated by their dynamic association with the adenosine nucleotides (ATP and ADP), as well as by their interaction with cochaperones and client proteins. In humans there are several Hsp70 proteins, most of which are found in the cytoplasm, while others are specific for organelles. The objective of this work was to structurally and functionally characterize the cytosolic (HspA8) and endoplasmic reticulum (HspA5) human Hsp70 proteins, using similar methodologies.For this, the recombinant hHsp70 proteins were expressed, purified and then characterized for structure, stability and function by means of biophysical tests. The results show that the HspA5 and HspA8 proteins were produced in their folded form, with secondary structure content rich in α-helices and as slightly elongated monomers in solution. Such Hsp70 showed similar chemical and thermal stability, however two thermal transitions (Tm) were observed for HspA5 and three for HspA8, indicating structural differences that result in distinct thermal stability. Changes in secondary and tertiary structure were observed in the proteins under study in the presence of nucleotides, which also caused the thermal stabilization of hHsp70. The presence of Ca 2+ and Mg 2+ ions favored the binding of hHsp70 to ATP and ADP nucleotides in different ways, and unlike HspA5, the HspA8 protein interacted with Ca 2+ even in the absence of nucleotides. A process thermodynamically governed by enthalpy and entropy was observed for the interaction of the adenosine nucleotides with the HspA5 and HspA8 proteins. hHsp70 showed similar and relatively low ATP activity, however the affinity of HspA5 for ATP was higher than that of HspA8. Additionally, the HspA5 and HspA8 proteins were effective in preventing the aggregation of model client proteins, with different specificities. In summary, the data obtained demonstrate that, although they share 66% of identity, the human proteins HspA5 and HspA8 present structural and functional peculiarities, thus enriching the knowledge about such macromolecules.

show abstract

Quantitative proteomics analysis reveals novel insights into mechanisms of action of disulfiram (DSF)

Zheng

Liu

et al. 2021

Proteomics Clinical Apps

View full text Add to dashboard Cite

Purpose Disulfiram (DSF) has been proven safe and shows the promising antitumor effect in preclinical studies. However, the precise mechanism of DSF on tumor is rarely reported. This study aims to fully understand the mechanism of action of DSF with a systems perspective in anticancer effects. Experimental Design SILAC‐based quantitative proteomics strategy was used to systematically identify differential expression proteins (DEPs) after DSF treatment in HeLa cells. Bioinformatical analysis (PANTHER, DAVID, and STRING) were performed to characterize biological functions of DEPs. Functional studies were performed to explore underlying mechanisms of DSF in cancer cells. Results In total, 201 proteins were dysregulated significantly after DSF exposure. Functional studies of hexokinase 2 (HK2), which catalyzed the first irreversible enzymatic step in glucose metabolism, revealed that various phenotypic effects observed after DSF treatment in cancer cells, at least partly, through the regulation of HK2 expression. Conclusions and Clinical Relevance By correlating the proteomics data with these functional studies, the current results provided novel insights into the mechanism underlying DSF function in cancer cells. Meanwhile, these provided theoretical basis for the new use of old drugs in clinical therapy.

show abstract

Hsp70 in cancer: A double agent in the battle between survival and death

Cited by 53 publications

References 233 publications

In Situ Vaccination as a Strategy to Modulate the Immune Microenvironment of Hepatocellular Carcinoma

In Situ Vaccination as a Strategy to Modulate the Immune Microenvironment of Hepatocellular Carcinoma

Caracterização estrutural, funcional e estabilidade térmica das proteínas humanas HspA5 e HspA8: uma abordagem comparativa

Quantitative proteomics analysis reveals novel insights into mechanisms of action of disulfiram (DSF)

Contact Info

Product

Resources

About