Silencing of GRP94 expression promotes apoptosis in pancreatic cancer cells

Zheng, Pan; Erkan, Mert; Streit, Sylvia; Friess, Helmut; Kleeff, Jörg

doi:10.3892/ijo_00000395

Cited by 17 publications

(3 citation statements)

References 30 publications

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“…[136] The cytoskeletal organizational and actin binding proteins like destrin, actin related protein 2/3 complex, subunit 2 (Arp2/3), Neural Wiskott-Aldrich syndrome protein (N-WASP), mitotic kinesin family member 14 (KIF14), Rho GDP dissociation inhibitor β (ARHGDIβ) and microtubule-associated protein (MAPRE2) were all associated with PNI regulation in PDA. [137,138,139,140] Rho/Rho kinase dependent Sema4D/plexin-B1 have been reported to be overexpressed in breast, prostatic and colon cancer PNI. [141] Chemokines CCL5-CCR5 and CXCL12/CXCR4 promote PNI due to increased actin polymerization as a result higher transmembrane Ca 2+ in SACC, breast and prostate cancer respectively.…”

Section: Actin and Actin Binding Proteinsmentioning

confidence: 99%

The Role of ECM Remodeling, EMT, and Adhesion Molecules in Cancerous Neural Invasion: Changing Perspectives

Mukherjee

Wai

et al. 2022

Advanced Biology

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the nerve, is often used synonymously with the term PNI. It is important to differentiate between these two terms as the former can be determined using imaging techniques as it is apparent both clinically and radiologically whereas the latter is more of a histological diagnosis. [4,5] The presence of PNI in malignant neoplasms serves as a marker for poor clinical prognosis and higher mortality rate among patients. PNI is most commonly detected in the aggressive pancreatic, prostate, head and neck, colorectal and gastric cancers. [6] Importantly, in some of these cancers, PNI is the only method of metastasis and it can exist independently without vascular and lymphatic invasion. [2,7] In head and neck, the prevalence of PNI varies between 25-80% when compared to non-PNI cases, whereas in pancreatic cancer, 90% of patients exhibit PNI. [8,9] Furthermore, multiple population-based studies carried out over the years have reported no significant difference in the development of PNI based on age, gender, ethnicity/race or other demographic risk factors like smoking history. [10,11,12] Knowledge of the structure and composition of the nerve and its perineural niche is integral to understanding PNI. The peripheral nerves are primarily composed of Schwann cells, fibroblasts, blood vessels along with axon bundles. The Schwann cells are essential for the maintenance of the axons as well as for the production of myelin in the peripheral nervous system. [13] The innermost endoneurium is composed of the extracellular matrix (ECM), fibroblasts and collagen. It is a delicate layer of connective tissue which wraps around the axon and capillaries. The axons are supported and protected by endoneurial cells which are found in this layer. [14] The perineurium has one or more layers of flat epithelial-like cells which group the axons and endoneurium into fascicles. The presence of tight and adherens junctions (AJs) in the epithelial layer adds to the robustness of this layer thereby providing a permeable, but selective barrier between the surrounding axons and tissues. [15] And finally, the outermost epineurium consists of a dense connective tissue layer composed of elastin fibers and collagen which surround the entire nerve bundle. [16] Numerous blood vessels can also be found in this layer as they serve as the vascular supply to the nerve. Based on the structure of the nerve, Leibig et al. [17] combined past and present definitions and defined PNI as the presence of cancer cells along the nerves Perineural invasion (PNI) refers to the cancerous invasion of nerves. It provides an alternative route for metastatic invasion and can exist independently in the absence of lymphatic or vascular invasion.It is a prominent characteristic of specific aggressive malignancies where it correlates with poor prognosis. The clinical significance of PNI is widely recognized despite a lack of understanding of the molecular mechanisms underlying its pathogenesis. The interaction between the nerve and the cancer cells is the most pivotal PNI step which...

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Section: Actin and Actin Binding Proteinsmentioning

confidence: 99%

The Role of ECM Remodeling, EMT, and Adhesion Molecules in Cancerous Neural Invasion: Changing Perspectives

Mukherjee

Wai

et al. 2022

Advanced Biology

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“…In colorectal cancer cells, a high expression of HSP90a has been associated with invasiveness and metastasis (Milicevic et al 2008). The HSP90 isoform GRP94 was reported to partly account for apoptosis resistance in pancreatic cancer cells (Pan et al 2009). …”

Section: Discussionmentioning

confidence: 99%

“…The most important HSP90 isoforms are the highly inducible HSP90a (HSP90AA) and the constitutively expressed HSP90b (HSP90AB), both of which are mostly found in the cytoplasm and constitute the HSP90A family (Csermely et al 1998, Sreedhar et al 2004, Chen et al 2005. Higher eukaryotes possess their own endoplasmatic reticulum (ER) isoform, glucose-related protein 94 (GRP94; Ni & Lee 2007), which constitutes the HSP90B family and is important for maintaining the ER-homeostasis (Pan et al 2009), as well as their own mitochondrial isoform TNF receptor-associated protein 1 (TRAP1; Csermely et al 1998), which is part of a mitochondrial pathway maintaining mitochondrial integrity (Kang et al 2007).…”

Section: Introductionmentioning

confidence: 99%

Expression and therapeutic relevance of heat-shock protein 90 in pancreatic endocrine tumors

Mayer

Harjung²,

Breinig³

et al. 2011

Endocrine-Related Cancer

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Pancreatic endocrine tumors (PET) represent a heterogenous group of neoplasms. Although surgical resection is considered a safe and effective treatment for many PET, therapeutic options for inoperable and progressive PET are limited. The expression of heat-shock protein (HSP) 90 was investigated in 120 clinically and pathomorphologically well-characterized PET from 84 patients using immunohistochemistry. In addition, in 19 snap-frozen PET and in three healthy pancreatic tissues, we performed immunoblot analyses, and in 15 snap-frozen PET and in three healthy pancreatic tissues, we investigated the expression of HSP90 isoforms by means of semiquantitative RT-PCR. Functional tests were conducted using the human pancreas carcinoid cell line BON and the mouse insulinoma cell line b-TC-3. HSP90 was expressed in 95% of the PET patients. The transcript levels of the HSP90 isoforms HSP90a, HSP90b, glucose-related protein 94, and TNF receptor-associated protein 1 were significantly increased in PET compared with non-neoplastic pancreatic tissues. The treatment of the cell lines BON and b-TC-3 with the HSP90 inhibitors 17-allylamino-17-demethoxygeldanamycin and 17-dimethylaminoethylamino-17-demethoxy-geldanamycin resulted in significant, dose-dependent reduction of cell viability, cell cycle arrest, and increased apoptosis. Furthermore, HSP90 inhibition induced the degradation and inactivation of several oncogenetic HSP90 client proteins in a time-and dose-dependent manner. HSP90 inhibitors increased the therapeutic effects of doxorubicin and 5-fluorucacil in BON and b-TC-3 cells. HSP90 is expressed in the vast majority of PET and its inhibition reveals significant treatment effects in vitro. Thus, HSP90 qualifies as a promising new target.

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Glucose-regulated protein 94 mediates cancer progression via AKT and eNOS in hepatocellular carcinoma

et al. 2015

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Hepatocellular carcinoma (HCC) is a crucial health issue worldwide. High glucose-regulated protein 94 (GRP94) expression has been observed in different types of cancer, suggesting a link between tumor progression and GRP94 expression. However, the mechanisms underlying the role of GRP94 in HCC progression remain unclear. We used specific small hairpin RNA (shRNA) to manipulate GRP94 expression in HCC cells. Tissue arrays, MTT assays, xCELLigence assays, and in vivo xenograft model were performed to identify clinicopathological correlations and to analyze cell growth. We found that high GRP94 expression reflected a poor response and a lower survival rate. In vitro and in vivo studies showed that silencing GRP94 suppressed cancer progression. Mechanistically, GRP94 knockdown reduced AKT, phospho-AKT, and eNOS levels but did not influence the AMPK pathway. Our results demonstrated that GRP94 is a key molecule in HCC progression that modulates the AKT pathway and eNOS levels. Our findings suggest that GRP94 may be a new prognostic and therapeutic target for HCC.

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Silencing of GRP94 expression promotes apoptosis in pancreatic cancer cells

Cited by 17 publications

References 30 publications

The Role of ECM Remodeling, EMT, and Adhesion Molecules in Cancerous Neural Invasion: Changing Perspectives

The Role of ECM Remodeling, EMT, and Adhesion Molecules in Cancerous Neural Invasion: Changing Perspectives

Expression and therapeutic relevance of heat-shock protein 90 in pancreatic endocrine tumors

Glucose-regulated protein 94 mediates cancer progression via AKT and eNOS in hepatocellular carcinoma

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