Hsp70 (HSP70A1A) downregulation enhances the metastatic ability of cancer cells

Kasioumi, Panagiota; Vrazeli, Paraskevi; Vezyraki, Patra; Zerikiotis, Stelios; Katsouras, Christos S.; Damalas, Alexander; Angelidis, Charalampos

doi:10.3892/ijo.2018.4666

Cited by 36 publications

(45 citation statements)

References 73 publications

(76 reference statements)

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“…Examination of E-cadherin expression revealed that it disappeared to a greater extent when tumor cells with downregulated Hsp70 were co-cultivated with monocytes, data that show Hsp70 knockdown leads to a more rapid and effective EMT ( Figure 5B). Our data correlate well with a very recent report by Kasioumi et al [43], who demonstrated that Hsp70 regulates the steps of metastasis, including EMT and migration. The absence of Hsp70 in cancer cells appears to be the destruction of the Hsp70-dependent heterocomplexes of E-cadherin/catenins, which function like an anchor between neighboring cells [43].…”

Section: Discussionsupporting

confidence: 93%

Extracellular Hsp70 Reduces the Pro-Tumor Capacity of Monocytes/Macrophages Co-Cultivated with Cancer Cells

Комарова

Marchenko

Zhakhov

et al. 2019

IJMS

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Cancer cells are known to contain high levels of the heat shock protein 70 kDa (Hsp70), which mediates increased cell proliferation, escape from programmed cell death, enhanced invasion, and metastasis. A part of Hsp70 molecules may release from cancer cells and affect the behavior of adjacent stromal cells. To explore the effects of Hsp70 on the status of monocytes/macrophages in the tumor locale, we incubated human carcinoma cells of three distinct lines with normal and reduced content of Hsp70 with THP1 monocytes. Using two methods, we showed that the cells with knock-down of Hsp70 released a lower amount of protein in the extracellular medium. Three cycles of the co-cultivation of cancer and monocytic cells led to the secretion of several cytokines typical of the tumor microenvironment (TME) and to pro-cancer activation of the monocytes/macrophages as established by elevation of F4/80 and arginase-1 markers. Unexpectedly, the efficacy of epithelial–mesenchymal transition and resistance of carcinoma cells to anticancer drugs after incubation with monocytic cells were more pronounced in cells with lower Hsp70, e.g., releasing less Hsp70 into the extracellular milieu. These data suggest that Hsp70 released from tumor cells into the TME is able, together with the development of an anti-cancer immune response, to limit the conversion of a considerable part of monocytic cells to the pro-tumor phenotype.

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Section: Discussionsupporting

confidence: 93%

Extracellular Hsp70 Reduces the Pro-Tumor Capacity of Monocytes/Macrophages Co-Cultivated with Cancer Cells

Комарова

Marchenko

Zhakhov

et al. 2019

IJMS

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“…In contrast, recent studies using small interfering RNA (siRNA) and short hairpin RNA (shRNA) have showed that HSP70 inactivation promotes cell transition to mesenchymal phenotype [185,190]. HSP70 downregulation destabilizes E-cadherin-catenin complexes allowing migration of tumor cells [185]. In addition, several reports have demonstrated that HSP70 inhibits TGF-β-induced EMT by decreasing Smad2 phosphorylation [191][192][193].…”

Section: Hsp70 In Metastasismentioning

confidence: 99%

“…Further research has found that inactivation of HSP70 showed to reduce tumor invasiveness and metastatic potential of breast, cervical and bladder cancer cell lines [183]. High HSP70 expression protects tumor cells against anoikis and amorphosis, forms of cell death that occur when cell loses its contact with extracellular matrix (ECM) [184,185]. In this regard, molecules involved in anoikis and amorphosis such as focal adhesion kinase (FAK) and Akt showed to be affected by HSP70 [186][187][188].…”

Section: Hsp70 In Metastasismentioning

confidence: 99%

“…Li and colleagues demonstrated that HSP70-peptide complexes (HSP70-PC) extracted from hepatocarcinoma samples induce EMT in human hepatoma (Huh-7) cell line acting through p38 MAPK signalling pathway [189]. In contrast, recent studies using small interfering RNA (siRNA) and short hairpin RNA (shRNA) have showed that HSP70 inactivation promotes cell transition to mesenchymal phenotype [185,190]. HSP70 downregulation destabilizes E-cadherin-catenin complexes allowing migration of tumor cells [185].…”

Section: Hsp70 In Metastasismentioning

confidence: 99%

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HSP70 Multi-Functionality in Cancer

Albakova

Армеев

Kanevskiy

et al. 2020

Cells

177

141

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The 70-kDa heat shock proteins (HSP70s) are abundantly present in cancer, providing malignant cells selective advantage by suppressing multiple apoptotic pathways, regulating necrosis, bypassing cellular senescence program, interfering with tumor immunity, promoting angiogenesis and supporting metastasis. This direct involvement of HSP70 in most of the cancer hallmarks explains the phenomenon of cancer “addiction” to HSP70, tightly linking tumor survival and growth to the HSP70 expression. HSP70 operates in different states through its catalytic cycle, suggesting that it can multi-function in malignant cells in any of these states. Clinically, tumor cells intensively release HSP70 in extracellular microenvironment, resulting in diverse outcomes for patient survival. Given its clinical significance, small molecule inhibitors were developed to target different sites of the HSP70 machinery. Furthermore, several HSP70-based immunotherapy approaches were assessed in clinical trials. This review will explore different roles of HSP70 on cancer progression and emphasize the importance of understanding the flexibility of HSP70 nature for future development of anti-cancer therapies.

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“…This is also good evidence of HSP70's contribution to cancer cell stemness because resistance to apoptosis is known to be one of the characteristic signs of CSCs (see the subsection introduction). Overall, except one publication describing rather hypothetical mechanisms by which HSP70 might suppress CSC phenotype development [119], all other reports testified that intracellular HSP70 promotes cancer cell stemness.…”

Section: Intracellular Hsp70mentioning

confidence: 99%

Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

Kabakov

Yakimova

Matchuk

2020

Cells

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Cancer stem cells (CSCs) are a great challenge in the fight against cancer because these self-renewing tumorigenic cell fractions are thought to be responsible for metastasis dissemination and cases of tumor recurrence. In comparison with non-stem cancer cells, CSCs are known to be more resistant to chemotherapy, radiotherapy, and immunotherapy. Elucidation of mechanisms and factors that promote the emergence and existence of CSCs and their high resistance to cytotoxic treatments would help to develop effective CSC-targeting therapeutics. The present review is dedicated to the implication of molecular chaperones (protein regulators of polypeptide chain folding) in both the formation/maintenance of the CSC phenotype and cytoprotective machinery allowing CSCs to survive after drug or radiation exposure and evade immune attack. The major cellular chaperones, namely heat shock proteins (HSP90, HSP70, HSP40, HSP27), glucose-regulated proteins (GRP94, GRP78, GRP75), tumor necrosis factor receptor-associated protein 1 (TRAP1), peptidyl-prolyl isomerases, protein disulfide isomerases, calreticulin, and also a transcription heat shock factor 1 (HSF1) initiating HSP gene expression are here considered as determinants of the cancer cell stemness and potential targets for a therapeutic attack on CSCs. Various approaches and agents are discussed that may be used for inhibiting the chaperone-dependent development/manifestations of cancer cell stemness.

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Hsp70 (HSP70A1A) downregulation enhances the metastatic ability of cancer cells

Cited by 36 publications

References 73 publications

Extracellular Hsp70 Reduces the Pro-Tumor Capacity of Monocytes/Macrophages Co-Cultivated with Cancer Cells

Extracellular Hsp70 Reduces the Pro-Tumor Capacity of Monocytes/Macrophages Co-Cultivated with Cancer Cells

HSP70 Multi-Functionality in Cancer

Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

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