HSP90 as a novel molecular target in non-small-cell lung cancer

Esfahani, Khashayar; Cohen, Victor

doi:10.2147/lctt.s60344

Cited by 21 publications

(12 citation statements)

References 36 publications

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“…Previous studies have shown that Akt1 interacts with the heat shock protein 90 (Hsp90) ( Sato et al, 2000 ; Esfahani and Cohen, 2016 ; Giulino-Roth et al, 2017 ). Interestingly, Hsp90 is a binding partner of HAX-1 ( Lam et al, 2013 , 2015 ).…”

Section: Resultsmentioning

confidence: 99%

“…In a previous study, HAX-1 was reported to interact with Hsp90 ( Lam et al, 2013 , 2015 ), a chaperone protein. Hsp90 assists other proteins to fold properly and can stabilize a number of proteins involved in tumor growth, which makes Hsp90 an investigatory target in cancer research ( Esfahani and Cohen, 2016 ). In particular, HAX-1 has been reported in recent years to combine with Hsp90 to adjust the expression of Cyclophilin-D and IRE-1, which can separately regulate the mitochondrial apoptosis and ER stress-related apoptosis ( Lam et al, 2013 , 2015 ).…”

Section: Discussionmentioning

confidence: 99%

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HAX-1 Protects Glioblastoma Cells from Apoptosis through the Akt1 Pathway

Deng

Song

Zhao

et al. 2017

Front. Cell. Neurosci.

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Glioblastoma is the most common malignant tumor in central nervous system (CNS), and it is still insurmountable and has a poor prognosis. The proliferation and survival mechanism of glioma cells needs to be explored further for the development of glioma treatment. Hematopoietic-substrate-1 associated protein X-1 (HAX-1) has been reported as an anti-apoptosis protein that plays an important role in several malignant tumors. However, the effect and mechanism of HAX-1 in glioblastomas remains unknown. This study aimed to investigate the effect of HAX-1 in glioblastoma cells and explore the mechanism. The results of clone formation and Edu proliferation assay showed slower multiplication in HAX-1 knock-out cells. Flow cytometry showed cell cycle arrest mainly in G0/G1 phase. Apoptosis due to oxidative stress was increased after HAX-1 was knocked out. Western-blot assay exhibited that the levels of p21, Bax, and p53 proteins were significantly raised, and that the activation of the caspase cascade was enhanced in the absence of HAX-1. The degradation rate and ubiquitination of p53 declined because of the decrease in phosphorylation of proteins MDM2 and Akt1. Co-immunoprecipitation (Co-IP) and immunefluorescent co-localization assays were performed to test the influence of HAX-1 on the interaction between Akt1 and Hsp90, which is crucial for the activity of Akt1. In conclusion, this novel study suggested that HAX-1 could affect the Akt1 pathway through Hsp90. The knock-out of HAX-1 leads to the inactivity of the Ak1t/MDM2 axis, which leads to increased levels of p53, and finally generates cell cycle arrest and results in the apoptosis of glioblastoma cells.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

HAX-1 Protects Glioblastoma Cells from Apoptosis through the Akt1 Pathway

Deng

Song

Zhao

et al. 2017

Front. Cell. Neurosci.

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“…Due to of their strong dependence on HSP90, inhibition of the latter leads to ubiquitin-mediated proteasomal degradation of client proteins concluding with the downregulation of different oncogenic signalling pathways [19]. Since EGFR [20], BRAF [21], ERBB2 [22], MET [23,24] and the EML4-ALK translocation product [8] are clients of HSP90, acting as oncodrivers in different clinico-pathological subsets of lung adenocarcinoma, degradation of these oncoproteins through HSP90 inhibition leads to loss of tumor-cell viability [25,26,27,28]. Promising results have been shown in different clinical studies, especially in malignancies that possess an HSP90 client as an oncodriver [29,30,31].…”

Section: Introductionmentioning

confidence: 99%

Impact of Heat Shock Protein 90 Inhibition on the Proteomic Profile of Lung Adenocarcinoma as Measured by Two-Dimensional Electrophoresis Coupled with Mass Spectrometry

Marrugal

Ferrer

Pastor

et al. 2019

Cells

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Heat shock protein 90 (HSP90) is an important chaperone in lung adenocarcinoma, with relevant protein drivers such as EGFR (epidermal growth factor receptor) and EML4-ALK (echinoderm microtubule-associated protein-like protein4 fused to anaplastic lymphoma kinase) depending on it for their correct function, therefore HSP90 inhibitors show promise as potential treatments for lung adenocarcinoma. To study responses to its inhibition, HSP90 was pharmacologically interrupted by geldanamycin and resorcinol derivatives or with combined inhibition of HSP90 plus HSP70 in lung adenocarcinoma cell lines. Two-dimensional electrophoresis was performed to identify proteomic profiles associated with inhibition which will help to understand the biological basis for the responses. HSP90 inhibition resulted in altered protein profiles that differed according the treatment condition studied. Results revealed 254 differentially expressed proteins after treatments, among which, eukaryotic translation initiation factor3 subunit I (eIF3i) and citrate synthase demonstrated their potential role as response biomarkers. The differentially expressed proteins also enabled signalling pathways involved in responses to be identified; these included apoptosis, serine-glycine biosynthesis and tricarboxylic acid cycle. The proteomic profiles identified here contribute to an improved understanding of HSP90 inhibition and open possibilities for the detection of potential response biomarkers which will be essential to maximize treatment efficacy in lung adenocarcinoma.

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“…Loss of the globular domain in EML4-ALK results in a relatively unstable fusion protein which recruits HSP90 [137]. Therefore, EML4-ALK variant 1 is sensitive to HSP90 inhibitor treatment and clinical trials in NSCLC patients using these inhibitors have shown promising results [142].…”

Section: Other Alk Fusion Proteins Are Causative Of Cancermentioning

confidence: 99%

The Transcriptional Roles of ALK Fusion Proteins in Tumorigenesis

Ducray

Natarajan

Garland

et al. 2019

Cancers

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Anaplastic lymphoma kinase (ALK) is a tyrosine kinase involved in neuronal and gut development. Initially discovered in T cell lymphoma, ALK is frequently affected in diverse cancers by oncogenic translocations. These translocations involve different fusion partners that facilitate multimerisation and autophosphorylation of ALK, resulting in a constitutively active tyrosine kinase with oncogenic potential. ALK fusion proteins are involved in diverse cellular signalling pathways, such as Ras/extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3K)/Akt and Janus protein tyrosine kinase (JAK)/STAT. Furthermore, ALK is implicated in epigenetic regulation, including DNA methylation and miRNA expression, and an interaction with nuclear proteins has been described. Through these mechanisms, ALK fusion proteins enable a transcriptional programme that drives the pathogenesis of a range of ALK-related malignancies.

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HSP90 as a novel molecular target in non-small-cell lung cancer

Cited by 21 publications

References 36 publications

HAX-1 Protects Glioblastoma Cells from Apoptosis through the Akt1 Pathway

HAX-1 Protects Glioblastoma Cells from Apoptosis through the Akt1 Pathway

Impact of Heat Shock Protein 90 Inhibition on the Proteomic Profile of Lung Adenocarcinoma as Measured by Two-Dimensional Electrophoresis Coupled with Mass Spectrometry

The Transcriptional Roles of ALK Fusion Proteins in Tumorigenesis

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