“Heat shock protein 70 in pancreatic diseases: Friend or foe”

Giri, Bhuwan; Sethi, Vrishketan; Modi, Shrey; Garg, Bharti; Banerjee, Sulagna; Saluja, Ashok K.; Dudeja, Vikas

doi:10.1002/jso.24653

Cited by 40 publications

(33 citation statements)

References 82 publications

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“…The water-soluble pro-drug of triptolide, Minnelide, was recently reported to show promising activity in patients with gastrointestinal malignancies in Phase I clinical trial 21,22 . Multiple mechanisms underlying TPL-induced antitumor activity have been described in the literature including inhibition of NFκB, c-Myc, HSP70 [23][24][25][26][27][28][29][30] , and XPB (ERCC3) 31 . Among them, inhibition of the ATPase activity of the XPB subunit of the transcription factor complex TFIIH is supported by biochemical evidence, which shows direct covalent binding of triptolide to XPB 32 .…”

Section: Introductionmentioning

confidence: 99%

Triptolide targets super-enhancer networks in pancreatic cancer cells and cancer-associated fibroblasts

Noel

Hussein

et al. 2020

Oncogenesis

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The tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) is highly heterogeneous, fibrotic, and hypovascular, marked by extensive desmoplasia and maintained by the tumor cells, cancer-associated fibroblasts (CAFs) and other stromal cells. There is an urgent need to identify and develop treatment strategies that not only target the tumor cells but can also modulate the stromal cells. A growing number of studies implicate the role of regulatory DNA elements called super-enhancers (SE) in maintaining cell-type-specific gene expression networks in both normal and cancer cells. Using chromatin activation marks, we first mapped SE networks in pancreatic CAFs and epithelial tumor cells and found them to have distinct SE profiles. Next, we explored the role of triptolide (TPL), a natural compound with antitumor activity, in the context of modulating cell-type-specific SE signatures in PDAC. We found that TPL, cytotoxic to both pancreatic tumor cells and CAFs, disrupted SEs in a manner that resulted in the downregulation of SE-associated genes (e.g., BRD4, MYC, RNA Pol II, and Collagen 1) in both cell types at mRNA and protein levels. Our observations suggest that TPL acts as a SE interactive agent and may elicit its antitumor activity through SE disruption to re-program cellular cross talk and signaling in PDAC. Based on our findings, epigenetic reprogramming of transcriptional regulation using SE modulating compounds such as TPL may provide means for effective treatment options for pancreatic cancer patients.

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Section: Introductionmentioning

confidence: 99%

Triptolide targets super-enhancer networks in pancreatic cancer cells and cancer-associated fibroblasts

Noel

Hussein

et al. 2020

Oncogenesis

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“…Secondly, we treated acinar cells from C mice with KRIBB11and found that HSF1 inhibition accelerated the death/necrosis and structural collapse of acinar cells (Additional le 1: Fig. S2C), which suggested that the core role of HSF1/HSPs on the protection of pancreas in stress condition [24]. Next, we treated acinar cells from KC mice with KRIBB11 and found that HSF1 inhibition suppressed the formation of ductal-like spheres, in other words, KRIBB11 inhibited the pancreatic cancer tumorigenesis in vitro (Additional le 1: Fig.…”

Section: Resultsmentioning

confidence: 96%

“…Driven by the KRAS oncogene mutation caused abnormal activation of multiple pathways (mainly on Ras-MAPK and PI3K-AKT-mTOR pathways [30]), the homeostasis of acinar cells was remolding [6] and the phenotype of pancreatic acinar cells gradually transforms from acinar cells to ductal-like cells (acinar cells undergo ADM); in this process, the transcriptome of acinar cells changed (the loss of acinar markers amylase and the gain of ductal markers CK19) [31]. Mentionable, HSF1/HSPs are important for the maintenance of the proteostasis of cells (including normal pancreatic acinar cells) in various stress condition and protect them against the damage of PTSs such as pancreatitis [24]. In this study, we found that EGFR-HSF1 axis was important for Kras oncogene mutation induced abnormal MAPK pathway activation driven PTSs and pancreatic cancer tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

The EGFR-HSF1 Axis Accelerates the Tumorigenesis of Pancreatic Cancer

Qian

Chen

Qin

et al. 2020

Preprint

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Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant diseases because of its non-symptomatic tumorigenesis. We previous found heat shock factor 1 (HSF1) was critical for PDAC progression and the aim of this study was to clarified the mechanisms on early activation of HSF1 and its role in the pancreatic cancer tumorigenesis. Methods: The expression and location of HSF1 on human or mice pancreatic tissues were examined by immunohistochemically staining. We mainly used pancreatic acinar cell 3-dimensional (3D) culture and a spontaneous pancreatic precancerous lesion mouse model called LSL-KrasG12D/+; Pdx1-Cre (KC) (and pancreatitis models derived from KC mice) to explore the pro-tumorigenesis mechanisms of the HSF1 in vitro and in vivo. Bioinformatics and molecular experiments were used to explore the underlying mechanisms between HSF1 and EGFR. Results: In this study, we found that pharmacological inhibition of HSF1 slowed pancreatic cancer initiation and suppressed the pancreatitis-induced formation of pancreatic precancerous lesion. Next, bioinformatics analysis revealed the closely linked between HSF1 and epidermal growth factor receptor (EGFR) pathway and we also confirmed their parallel activation in pancreatic precancerous lesions. Besides, the pharmacological inhibition of EGFR suppressed the initiation of pancreatic cancer and the activation of HSF1 in vivo. Indeed, we demonstrated that the EGFR activation that mediated pancreatic cancer tumorigenesis was partly HSF1-dependent in vitro.Conclusion: Hence, we concluded that the EGFR-HSF1 axis promoted the initiation of pancreatic cancer.

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“…All these imply that Hsp70 members play an important role in cancer. Previous studies indicate that Hsp70A1A is involved in pancreatic cancer and hepatocellular carcinoma [32,33], but the relationship between Hsp70A1B and tumor progression and the mechanism which involved in is still not well defined. Our previous research found that Single cell RNA sequencing of T cells confirmed that HspA1B was up regulated in activated CD8+ T and Treg cells and represses CD8+ T cell functions in vitro.…”

Section: Introductionmentioning

confidence: 99%

HspA1BIs a Prognostic Biomarker and Correlated With Immune Infiltrates in different subtypes of Breast Cancers

Wang

2019

Preprint

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Background: Heat shock A1B, also known as HSP70kDa protein 1B, encodes a 70kDa heat shock protein which is a member of the heat shock protein 70 family. HspA1B is a critical gene which related to many type of diseases by involving in the ubiquitin-proteasome pathway. However, the correlations of HspA1B to prognosis and tumor-infiltrating lymphocytes in different cancers remain unclear. Methods: HspA1B expression was evaluated on the Oncomine database and Tumor Immune Estimation Resource (TIMER) site. We analyzed the influence of HspA1B on clinical prognosis using Kaplan-Meier plotter, the PrognoScan database and Gene Expression Profiling Interactive Analysis (GEPIA). The correlations between HspA1B and cancer immune infiltrates was investigated via TIMER. In addition, correlations between HspA1B expression and gene marker sets of immune infiltrates were analyzed by TIMER and GEPIA. Results: Three cohorts (GSE9195, GSE9893, GSE3494-GPL96)) of breast cancer patients showed that high HspA1B expression was associated with poorer overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS). In addition, high HspA1B expression was significantly correlated with poor OS and progression-free survival (PFS) in bladder cancer, brain cancer and skin cancer. Moreover, HspA1B significantly impacts the prognosis of diverse cancers via The Cancer Genome Atlas (TCGA). HspA1B expression was positively correlated with infiltrating levels of CD4+ T and CD8+ T cells, macrophages, neutrophils, and dendritic cells (DCs) indifferent subtypes of Breast cancer. HspA1B expression showed strong correlations with diverse immune marker sets in BRCA-Luminal. Conclusions: Our findings suggest that HspA1B is correlated with prognosis and immune infiltrating levels of, including those of CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and DCs in multiple cancers, especially in colon and gastric cancer patients. In addition, HspA1B expression potentially contributes to regulation of tumor-associated macrophages (TAMs), DCs, T cell exhaustion and Tregs in colon and gastric cancer. These findings suggest that HspA1B can be used as a prognostic biomarker for determining prognosis and immune infiltration in BRCA-Luminal subtype.

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“Heat shock protein 70 in pancreatic diseases: Friend or foe”

Cited by 40 publications

References 82 publications

Triptolide targets super-enhancer networks in pancreatic cancer cells and cancer-associated fibroblasts

Triptolide targets super-enhancer networks in pancreatic cancer cells and cancer-associated fibroblasts

The EGFR-HSF1 Axis Accelerates the Tumorigenesis of Pancreatic Cancer

HspA1BIs a Prognostic Biomarker and Correlated With Immune Infiltrates in different subtypes of Breast Cancers

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