HSP‐enriched properties of extracellular vesicles involve survival of metastatic oral cancer cells

Ono, Koji; Eguchi, Takanori; Sogawa, Chiharu; Calderwood, Stuart K.; Futagawa, Junya; Kasai, Tomonari; Seno, Masaharu; Okamoto, Kuniaki; Sasaki, Akira; Kozaki, Ken Ichi

doi:10.1002/jcb.27039

Cited by 133 publications

(169 citation statements)

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“…It has been shown that HSPs are often increased in tumor cells and are involved in the properties of tumor progression such as increased migration, invasion, and metastasis [17,18]. Additionally, extracellular HSPs are released from cells with vesicles as well as a soluble form [4,19,20]. Notably, HSPs and vesicles were co-released upon cell stress and cell damage such as molecular targeted therapeutic stress [21,22], anticancer therapeutic DNA damage stress [23,24], and HSS [25,26].…”

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confidence: 99%

“…In addition, the enhancement of EMT properties was often coupled with increased release of EVs [22,49]. These facts prompted us to make a concept of EMT-coupled vesicle release.Among many molecular cargos, HSPs are major signatures often found within sEV such as exosomes, ectosomes, and oncosomes [4,19,20,27]. According to the minimal information for studies of extracellular vesicles 2018 (MISEV2018), EV markers are categorized into five categories and the category 2 (cytosolic proteins recovered in EVs) includes heat shock cognate 70 (HSC70/HSPA8: essential for autophagy), HSP70, and HSP90β (HSP90AB1/HSP84), while category 4 (transmembrane, lipid-bound, and soluble proteins associated to other intracellular compartments than plasma membrane/endosomes) includes ER chaperones such as Grp94/HSP90B and BiP/HSPA5 [29].…”

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confidence: 99%

“…Moreover, sEV derived from oral cancer cells contained a variety of HSPs, including HSP90α (HSP90AA1), HSP90β, TRAP1 (mitochondrial HSP90), HSP105, HSP70 (HSP72/HSPA1A and HSP70B'/HSPA6), GRP78/HSPA5 (ER chaperone), and HSC70 [20]. Among these HSPs, two HSP90 isoforms (HSP90α and HSP90β) were enriched in sEV derived from high metastatic cancer cells compared to low metastatic ones [20].…”

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confidence: 99%

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Cell Stress Induced Stressome Release Including Damaged Membrane Vesicles and Extracellular HSP90 by Prostate Cancer Cells

Eguchi

Sogawa

Ono

et al. 2020

Cells

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Tumor cells exhibit therapeutic stress resistance-associated secretory phenotype involving extracellular vesicles (EVs) such as oncosomes and heat shock proteins (HSPs). Such a secretory phenotype occurs in response to cell stress and cancer therapeutics. HSPs are stress-responsive molecular chaperones promoting proper protein folding, while also being released from cells with EVs as well as a soluble form known as alarmins. We have here investigated the secretory phenotype of castration-resistant prostate cancer (CRPC) cells using proteome analysis. We have also examined the roles of the key co-chaperone CDC37 in the release of EV proteins including CD9 and epithelial-to-mesenchymal transition (EMT), a key event in tumor progression. EVs derived from CRPC cells promoted EMT in normal prostate epithelial cells. Some HSP family members and their potential receptor CD91/LRP1 were enriched at high levels in CRPC cell-derived EVs among over 700 other protein types found by mass spectrometry. The small EVs (30–200 nm in size) were released even in a non-heated condition from the prostate cancer cells, whereas the EMT-coupled release of EVs (200–500 nm) and damaged membrane vesicles with associated HSP90α was increased after heat shock stress (HSS). GAPDH and lactate dehydrogenase, a marker of membrane leakage/damage, were also found in conditioned media upon HSS. During this stress response, the intracellular chaperone CDC37 was transcriptionally induced by heat shock factor 1 (HSF1), which activated the CDC37 core promoter, containing an interspecies conserved heat shock element. In contrast, knockdown of CDC37 decreased EMT-coupled release of CD9-containing vesicles. Triple siRNA targeting CDC37, HSP90α, and HSP90β was required for efficient reduction of this chaperone trio and to reduce tumorigenicity of the CRPC cells in vivo. Taken together, we define “stressome” as cellular stress-induced all secretion products, including EVs (200–500 nm), membrane-damaged vesicles and remnants, and extracellular HSP90 and GAPDH. Our data also indicated that CDC37 is crucial for the release of vesicular proteins and tumor progression in prostate cancer.

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Cell Stress Induced Stressome Release Including Damaged Membrane Vesicles and Extracellular HSP90 by Prostate Cancer Cells

Eguchi

Sogawa

Ono

et al. 2020

Cells

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“…Conversely, cetuximab increased EGFR phosphorylation in OSC-19 cells, although Akt phosphorylation was still inhibited by cetuximab in this cell line. Recently, it was demonstrated that HNSCC secreted cetuximab with EGFR-containing extracellular vesicles (44,45). OSC-19 cells may incorporate cetuximab-bound EGFR in the cytoplasm following EGFR phosphorylation, and the cetuximab-bound EGFR may be excluded by this novel mechanism.…”

Section: Discussionmentioning

confidence: 99%

Nicotine promotes lymph node metastasis and cetuximab resistance in head and neck squamous cell carcinoma

et al. 2018

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Epidermal growth factor (EGF) is overexpressed in many cancers and is associated with worse prognosis. EGF binds to its cell surface receptor (EGFR), which induces EGFR phosphorylation. Phosphorylated EGFR (p-EGFR) is translocated into the nucleus, which increases cancer cell activity. Nicotine, which is one of the main components of tobacco, is absorbed through pulmonary alveoli and mucosal epithelia in the head and neck region by smoking and moves into the blood. Nicotine in blood binds to nicotinic acetylcholine receptor (nAChR) in the central nervous system and serves a crucial role in tobacco addiction. Although nAChR localization is thought to be limited in the nervous system, nAChR is present in a wide variety of non-neuronal cells, including cancer cells. Recent studies suggest that nicotine contributes to the metastasis and resistance to anti-cancer drugs of various cancer cells. However, it remains unknown whether head and neck squamous cell carcinoma (HNSCC) cells can utilize nicotine-nAChR signaling to metastasize and acquire resistance to anti-cancer drugs, even though the mucosal epithelia of the head and neck region are the primary sites of exposure to tobacco smoke. To the best of our knowledge, the present study is the first to demonstrate the role of nicotine in metastasis and anti-EGFR-therapy resistance of HNSCC. The present findings demonstrated that nicotine increased proliferation, migration, invasion, p-EGFR nuclear translocation and protein kinase B (Akt) phosphorylation in HNSCC cells. It was also demonstrated that nicotine restored cetuximab-inhibited proliferation, migration and invasion of HNSCC cells. Finally, an in vivo experiment revealed that nicotine increased lymph node metastasis of xenografted tumors, whereas an nAChR inhibitor suppressed lymph node metastasis and p-EGFR nuclear localization of xenografted tumors. Taken together, these results demonstrated that nicotine induced nuclear accumulation of p-EGFR, and activation of Akt signaling. These signaling pathways elevated the activities of HNSCC cells, causing lymph node metastasis and serving a role in cetuximab resistance.

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“…Altogether these results confirm the interest of targeting HSP110, at least in colorectal cancers, and probably in other types of cancer, such as B-cell lymphoma. Although HSPs are generally considered intracellular proteins, we now know that HSP110 can also be released to act extracellularly like HSP27, 70, and 90 [157][158][159]. The release of HSP110 from human intestinal epithelial cells has also been described, suggesting a role in the physiological process of epithelial renewal [160].…”

Section: Hsp110 Functionsmentioning

confidence: 99%

Chaperoning STAT3/5 by Heat Shock Proteins: Interest of Their Targeting in Cancer Therapy

Hermetet

Girodon

Jego

2019

Cancers

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While cells from multicellular organisms are dependent upon exogenous signals for their survival, growth, and proliferation, commitment to a specific cell fate requires the correct folding and maturation of proteins, as well as the degradation of misfolded or aggregated proteins within the cell. This general control of protein quality involves the expression and the activity of molecular chaperones such as heat shock proteins (HSPs). HSPs, through their interaction with the STAT3/STAT5 transcription factor pathway, can be crucial both for the tumorigenic properties of cancer cells (cell proliferation, survival) and for the microenvironmental immune cell compartment (differentiation, activation, cytokine secretion) that contributes to immunosuppression, which, in turn, potentially promotes tumor progression. Understanding the contribution of chaperones such as HSP27, HSP70, HSP90, and HSP110 to the STAT3/5 signaling pathway has raised the possibility of targeting such HSPs to specifically restrain STAT3/5 oncogenic functions. In this review, we present how HSPs control STAT3 and STAT5 activation, and vice versa, how the STAT signaling pathways modulate HSP expression. We also discuss whether targeting HSPs is a valid therapeutic option and which HSP would be the best candidate for such a strategy.

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HSP‐enriched properties of extracellular vesicles involve survival of metastatic oral cancer cells

Cited by 133 publications

References 49 publications

Cell Stress Induced Stressome Release Including Damaged Membrane Vesicles and Extracellular HSP90 by Prostate Cancer Cells

Cell Stress Induced Stressome Release Including Damaged Membrane Vesicles and Extracellular HSP90 by Prostate Cancer Cells

Nicotine promotes lymph node metastasis and cetuximab resistance in head and neck squamous cell carcinoma

Chaperoning STAT3/5 by Heat Shock Proteins: Interest of Their Targeting in Cancer Therapy

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