A potentially common peptide target in secreted heat shock protein-90α for hypoxia-inducible factor-1α–positive tumors

Sahu, Divya; Zhao, Zhengwei; Tsen, Fred; Cheng, Chieh-Fang; Park, Ryan; Situ, Alan J.; Dai, Jinyao; Eginli, Ariana; Shams, Sharmineh; Chen, Mei; Ulmer, Tobias S.; Conti, Peter; Woodley, David T.; Li, Wei

doi:10.1091/mbc.e11-06-0575

Cited by 66 publications

(92 citation statements)

References 50 publications

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“…MMP2 is involved in the breakdown of extracellular matrix in normal physiological processes, and altered MMP2 expression contributes to human disease, including cancer development and progression. Another study showed a potentially common peptide target in secreted Hsp90a for hypoxia-inducible factor-1a-positive cancers (14). The authors localized the tumor-promoting effect of Hsp90a to a 115-amino acid region of secreted Hsp90a protein, maintenance of which was sufficient to bypass the blockade of HIF1a depletion and resumed tumor invasion, suggesting that drugs that target these amino acid region could be more effective and less toxic in the treatment of HIF1a-positive cancers (14).…”

Section: Discussionmentioning

confidence: 99%

“…Another study showed a potentially common peptide target in secreted Hsp90a for hypoxia-inducible factor-1a-positive cancers (14). The authors localized the tumor-promoting effect of Hsp90a to a 115-amino acid region of secreted Hsp90a protein, maintenance of which was sufficient to bypass the blockade of HIF1a depletion and resumed tumor invasion, suggesting that drugs that target these amino acid region could be more effective and less toxic in the treatment of HIF1a-positive cancers (14). Thus, altered expression of Hsp90a protein could serve as a biomarker for different human cancers.…”

Section: Discussionmentioning

confidence: 99%

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Plasma Levels of Heat Shock Protein 90 Alpha Associated with Lung Cancer Development and Treatment Responses

Shi

Xiaoqing

Lou

et al. 2014

Clinical Cancer Research

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Purpose: Altered expression of heat shock protein 90 alpha (Hsp90a) was associated with tumor development, progression, and metastasis. This study explored plasma levels of Hsp90a protein in patients with lung cancer and other controls to assess its diagnostic value and monitor treatment responses for patients with lung cancer.Experimental Design: A total of 2,247 individuals were recruited and assigned into two cohorts as static and dynamic groups. ELISA analysis and confirmation of plasma Hsp90a protein levels for association with tumor stages and treatment responses, respectively, were performed.Results: The average plasma levels of Hsp90a protein in patients with lung cancer were significantly higher than in healthy controls (P < 0.0001). Plasma levels of Hsp90a protein in patients with advanced lung cancer (stage III-IV) were higher than in patients with early-stage lung cancer (stage I-II; P < 0.001). Using a cutoff value of 56.33 ng/mL to separate lung cancer from other controls, the sensitivity and specificity reached 72.18% (95% CI, 0.695-0.749) and 78.70% (95% CI, 0.761-0.813), respectively. To confirm the different levels in the second cohort, plasma levels of Hsp90a protein showed a statistically significant difference between preoperative and postoperative patients in surgical patient groups (P < 0.007). There was also a statistically significant difference between the disease progressive group and stable disease group, with regard to partial response after chemotherapy (P < 0.0001).Conclusions: This study demonstrated that plasma Hsp90a protein levels are useful as a diagnostic biomarker in lung cancer and predict the responses of patients with lung cancer to chemotherapy. Clin Cancer Res; 20(23); 6016-22. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Plasma Levels of Heat Shock Protein 90 Alpha Associated with Lung Cancer Development and Treatment Responses

Shi

Xiaoqing

Lou

et al. 2014

Clinical Cancer Research

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“…Utilization of lentiviral systems for downregulation and overexpression of genes are as previously described (Li et al, 2007;Cheng et al, 2008;Sahu et al, 2012). The shRNA sequences for human Hsp90a was 59-GGAAAGAGCTGCATATTAA-39 (sense) and for human Hsp90b was 59-GCATCTATCGCATGATCAA-39 (sense).…”

Section: Chemotaxis Assaymentioning

confidence: 99%

Hsp90α and Hsp90β Co-Operate a Stress-Response Mechanism to Cope With Hypoxia and Nutrient Paucity during Wound Healing

Jayaprakash

Dong

Zou

et al. 2015

Journal of Cell Science

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When tissues are injured and blood vessels clot, the local environment becomes ischemic, meaning that there is a lack of adequate supply of oxygen and glucose delivered to the surrounding cells. The heat shock protein-90 (Hsp90) family proteins protect tissues from various environmental insults and participate in the repair of damaged tissue. Here, we report discovery of a new ischemia-responsive mechanism in which the two Hsp90 isoforms Hsp90a and Hsp90b (also known as HSP90AA1 and HSP90AB1, respectively) work together to promote cell motility in wounded skin and accelerate wound closure. We demonstrate that Hsp90a and Hsp90b have distinct and non-exchangeable functions during wound healing. Under hypoxia and when there is a lack of serum factors, Hsp90b binds to the cytoplasmic tail of the LDL receptor-related protein-1 (LRP-1) and stabilizes the receptor at the cell surface. Hsp90a, however, is secreted by the cell into extracellular space where it binds and signals through the LRP-1 receptor to promote cell motility, leading to wound closure. In addition to skin injury, we suggest that this repair mechanism applies broadly to other non-cutaneous injured tissues.

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“…The protocols for using lentiviral systems for gene downregulation and gene upregulation, including virus packaging, isolation, infection, and analyses, were as previously described (33,37,42). The pRRLsinh-CMV system was used to overexpress exogenous genes such as the wt and mutant PRAS40 cDNAs.…”

Section: Methodsmentioning

confidence: 99%

“…We used CRISPR/cas9 to NTA analysis of 100,000 ϫ g pellet fractions from conditioned medium of 3 ϫ 10 6 cells, as indicated. **, P Ͻ 0.05; ***, P Ͻ 0.005. knock out both alleles of the Hsp90␣ gene in MDA-MB-231 breast cancer cells (41) that have been shown to constitutively secrete exosomes and Hsp90␣ (42,43). As shown in Fig.…”

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confidence: 99%

PRAS40 Connects Microenvironmental Stress Signaling to Exosome-Mediated Secretion

Guo

Jayaprakash

Jian

et al. 2017

Molecular and Cellular Biology

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Secreted exosomes carrying lipids, proteins, and nucleic acids conduct cell-cell communications within the microenvironment of both physiological and pathological conditions. Exosome secretion is triggered by extracellular or intracellular stress signals. Little is known, however, about the signal transduction between stress cues and exosome secretion. To identify the linker protein, we took advantage of a unique finding in human keratinocytes. In these cells, although transforming growth factor alpha (TGF-␣) and epidermal growth factor (EGF) share the same EGF receptor and previously indistinguishable intracellular signaling networks, only TGF-␣ stimulation causes exosome-mediated secretion. However, deduction of EGF-activated pathways from TGF␣-activated pathways in the same cells allowed us to identify the proline-rich Akt substrate of 40 kDa (PRAS40) as the unique downstream effector of TGF-␣ but not EGF signaling via threonine 308-phosphorylated Akt. PRAS40 knockdown (KD) or PRAS40 dominant-negative (DN) mutant overexpression blocks not only TGF-␣-but also hypoxia-and H 2 O 2 -induced exosome secretion in a variety of normal and tumor cells. Site-directed mutagenesis and gene rescue studies show that Akt-mediated activation of PRAS40 via threonine 246 phosphorylation is both necessary and sufficient to cause exosome secretion without affecting the endoplasmic reticulum/Golgi pathway. Identification of PRAS40 as a linker protein paves the way for understanding how stress regulates exosome secretion under pathophysiological conditions.

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A potentially common peptide target in secreted heat shock protein-90α for hypoxia-inducible factor-1α–positive tumors

Cited by 66 publications

References 50 publications

Plasma Levels of Heat Shock Protein 90 Alpha Associated with Lung Cancer Development and Treatment Responses

Plasma Levels of Heat Shock Protein 90 Alpha Associated with Lung Cancer Development and Treatment Responses

Hsp90α and Hsp90β Co-Operate a Stress-Response Mechanism to Cope With Hypoxia and Nutrient Paucity during Wound Healing

PRAS40 Connects Microenvironmental Stress Signaling to Exosome-Mediated Secretion

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