Unusual Suspects in the Twilight Zone Between the Hsp90 Interactome and Carcinogenesis

Vartholomaiou, Evangelia; Echeverria, Pablo Christian; Picard, Didier

doi:10.1016/bs.acr.2015.08.001

Cited by 44 publications

(31 citation statements)

References 140 publications

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“…However several other inhibitors have been reported which disrupt chaperone cycle in ways other than binding to N terminal ATP binding pocket [146,147]. The most potent inhibitors with high significance, have natural origin, are accounted here (Fig.…”

Section: Hsp90 Inhibitorsmentioning

confidence: 95%

Hsp90: Friends, clients and natural foes

et al. 2016

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Section: Hsp90 Inhibitorsmentioning

confidence: 95%

Hsp90: Friends, clients and natural foes

et al. 2016

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“…Moreover, Hsp90 was found to interact with a number of proteins important for breast cancer, for example the hypoxia inducible factor HIF-1α, estrogen receptor α, anti-apoptotic kinase Akt, tumor suppressor protein p53, and the ErbB receptor tyrosine kinase (see https://www.picard.ch/downloads/Hsp90facts.pdf for a comprehensive overview and references). The Hsp90 chaperone machinery can be important for tumorigenic transformation due to its ability to stabilize overexpressed or mutated oncoproteins or transformation-relevant signaling pathways, thereby contributing to oncogene addiction and survival of cancer cells [4–6]. Hsp90α has been proposed to promote the motility, invasiveness and acquisition of stress resistance of cancer cells [7–9].…”

Section: Introductionmentioning

confidence: 99%

Cytosolic Hsp90α and its mitochondrial isoform Trap1 are differentially required in a breast cancer model

et al. 2017

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The Hsp90 family of molecular chaperones includes the cytosolic isoforms Hsp90a and Hsp90β and the mitochondrial isoform Trap1. Hsp90a/βsupport a large number of client proteins in the cytoplasm and the nucleus whereas Trap1 regulates oxidative phosphorylation in mitochondria. Many of the associated proteins and cellular processes are relevant to cancer, and there is ample pharmacological and genetic evidence to support the idea that Hsp90a/βand Trap1 are required for tumorigenesis. However, a direct and comparative genetic test in a mouse cancer model has not been done. Here we report the effects of deleting the Hsp90a or Trap1 genes in a mouse model of breast cancer. Neither Hsp90a nor Trap1 are absolutely required for mammary tumor initiation, growth and metastasis induced by the polyoma middle T-antigen as oncogene. However, they do modulate growth and lung metastasis in vivo and cell proliferation, migration and invasion of isolated primary carcinoma cells in vitro. Without Hsp90a, tumor burden and metastasis are reduced, correlating with impaired proliferation, migration and invasion of cells in culture. Without Trap1, the appearance of tumors is initially delayed, and isolated cells are affected similarly to those without Hsp90a. Analysis of expression data of human breast cancers supports the conclusion that this is a valid mouse model highlighting the importance of these molecular chaperones.

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“…Recently, the role of HSP90 in tumour cells has been highlighted. Numerous cancer proteins are substrates of HSP90, which depend on HSP90 mechanisms to fold and mature . For example, receptor tyrosine kinases, which are required for cancer development and progression, may interact with HSP90 leading to the uncontrolled proliferation of cancer cells .…”

Section: Discussionmentioning

confidence: 99%

“…Numerous cancer proteins are substrates of HSP90, which depend on HSP90 mechanisms to fold and mature. 25 For example, receptor tyrosine kinases, which are required for cancer development and progression, may interact with HSP90 leading to the uncontrolled proliferation of cancer cells. 5 In order to explain the broad requirements for HSPs, including HSP90 during cancer progression, Ciocca et al proposed a new hypothesis termed 'addiction to chaperones'.…”

Section: Discussionmentioning

confidence: 99%

Elevated HSP90 associates with expression of HIF‐1α and p‐AKT and is predictive of poor prognosis in nasopharyngeal carcinoma

et al. 2019

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Aims HSP90, as a molecular chaperone, has numerous substrate proteins, including HIF‐1α and p‐AKT, but the relationships among HSP90, HIF‐1α and p‐AKT have not been investigated in NPC. We examined and analysed the correlation between expression of HSP90, HIF‐1α and p‐AKT and clinicopathological features of NPC. Methods We collected 445 cases of NPC and 54 cases of non‐cancerous nasopharyngeal epithelia tissues, detected expression of HSP90, HIF‐1α and p‐AKT proteins in these tissues by immunohistochemistry. Results The results indicated that overexpression of HSP90, HIF‐1α and p‐AKT in NPC was significantly higher than that in non‐cancerous nasopharyngeal epithelia (P < 0.05). The overexpression of HIF‐1α in primary NPC was significantly lower than that in matched lymph node metastatic NPC (P = 0.024) or recurrent NPC (P = 0.039). The overexpression of HSP90 (P < 0.001) and HIF‐1α (P = 0.031) was evidently higher in late stage NPC. NPC patients with lymph node metastasis (LNM) had a higher overexpression rate of HSP90 (P < 0.001) than those without LNM. Increased HSP90 expression was positively associated with HIF‐1α expression (r = 0.367, P < 0.001) and p‐AKT (r = 0.142, P = 0.003) expression in NPC. Furthermore, HIF‐1α was also related to p‐AKT expression (r = 0.114, P = 0.017). The overall survival rate for NPC patients with up‐regulated HSP90 was significantly lower than those with down‐regulated HSP90 (P < 0.001), as was found with raised HIF‐1α (P = 0.036) and increased p‐AKT (P = 0.044). Multivariate Cox regression analysis further identified that HSP90 and HIF‐1α were independent poor prognostic factors for NPC. Conclusions Taken together, elevated HSP90 was associated with expression of HIF‐1α and p‐AKT in NPC. Furthermore, high expression of HSP90 and HIF‐1α could be used as a novel independent poor prognostic biomarker for patients with NPC.

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Unusual Suspects in the Twilight Zone Between the Hsp90 Interactome and Carcinogenesis

Cited by 44 publications

References 140 publications

Hsp90: Friends, clients and natural foes

Hsp90: Friends, clients and natural foes

Cytosolic Hsp90α and its mitochondrial isoform Trap1 are differentially required in a breast cancer model

Elevated HSP90 associates with expression of HIF‐1α and p‐AKT and is predictive of poor prognosis in nasopharyngeal carcinoma

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