Heat Shock Protein 90-α Mediates Aldo-Keto Reductase 1B10 (AKR1B10) Protein Secretion through Secretory Lysosomes

Luo, Dixian; Bu, Yiwen; Ma, Jun; Rajput, Sandeep; He, Yingchun; Cai, Guangyan; Liao, Duan‐Fang; Cao, Deliang

doi:10.1074/jbc.m113.514877

Cited by 24 publications

(26 citation statements)

References 37 publications

(22 reference statements)

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“…AKR1B10 was first identified in HCC and then characterized as a secretory protein . In the past years, clinical histological studies of HCC have identified AKR1B10 as a marker for prognosis and risk stratification of HCC .…”

Section: Discussionmentioning

confidence: 99%

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A Large‐Scale Multicenter Study Validates Aldo‐Keto Reductase Family 1 Member B10 as a Prevalent Serum Marker for Detection of Hepatocellular Carcinoma

et al. 2019

Hepatology

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Aldo‐keto reductase family 1 member B10 (AKR1B10) is a secretory protein overexpressed in hepatocellular carcinoma (HCC). We aimed to evaluate AKR1B10 as a serum marker for detection of HCC. Herein, we conducted a cohort study that consecutively enrolled 1,244 participants from three independent hospitals, including HCC, healthy controls (HCs), benign liver tumors (BLTs), chronic hepatitis B (CHB), and liver cirrhosis (LC). Serum AKR1B10 was tested by time‐resolved fluorescent assays. Data were plotted for receiver operating characteristic (ROC) curve analyses. Alpha‐fetoprotein (AFP) was analyzed for comparison. An exploratory discovery cohort demonstrated that serum AKR1B10 increased in patients with HCC (1,567.3 ± 292.6 pg/mL; n = 69) compared with HCs (85.7 ± 10.9 pg/mL; n = 66; P < 0.0001). A training cohort of 519 participants yielded an optimal diagnostic cutoff of serum AKR1B10 at 267.9 pg/mL. When ROC curve was plotted for HCC versus all controls (HC + BLT + CHB + LC), serum AKR1B10 had diagnostic parameters of the area under the curve (AUC) 0.896, sensitivity 72.7%, and specificity 95.7%, which were better than AFP with AUC 0.816, sensitivity 65.1%, and specificity 88.9%. Impressively, AKR1B10 showed promising diagnostic potential in early‐stage HCC and AFP‐negative HCC. Combination of AKR1B10 with AFP increased diagnostic accuracy for HCC compared with AKR1B10 or AFP alone. A validation cohort of 522 participants confirmed these findings. An independent cohort of 68 patients with HCC who were followed up showed that serum AKR1B10 dramatically decreased 1 day after operation and was nearly back to normal 3 days after operation. Conclusion : AKR1B10 is a potent serum marker for detection of HCC and early‐stage HCC, with better diagnostic performance than AFP.

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Section: Discussionmentioning

confidence: 99%

“…AKR1B10 is a secretory protein up‐regulated in HCC . AKR1B10 can eliminate cytotoxic and carcinogenic α and β‐unsaturated carbonyl compounds and regulate de novo fatty acid/lipid synthesis .…”

mentioning

confidence: 99%

A Large‐Scale Multicenter Study Validates Aldo‐Keto Reductase Family 1 Member B10 as a Prevalent Serum Marker for Detection of Hepatocellular Carcinoma

et al. 2019

Hepatology

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“…In agreement with our studies, HSP90α has been described in the cytoplasm of 3T3 cells (56, 57) and increased expression of HSP90 (58), and in particular, the isoform HSP90α (59) has been observed in cancer compared to that in normal tissue. Furthermore, recent studies have shown that HSP90 (60), including HSP90α, regulates the migration and invasion of cancer cells (57, 61) and can transport client proteins to lysosomes for secretion (62). Moreover, a variant of HSP90α has been shown to chaperone some proteins to exosomes in a variety of cancer cell lines (61).…”

Section: Discussionmentioning

confidence: 99%

Localization of MRP‐1 to the outer mitochondrial membrane by the chaperone protein HSP90β

2015

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Overexpression of plasma membrane multidrug resistance-associated protein 1 (MRP-1) in Ewing's sarcoma (ES) predicts poor outcome. MRP-1 is also expressed in mitochondria, and we have examined the submitochondrial localization of MRP-1 and investigated the mechanism of MRP-1 transport and role of this organelle in the response to doxorubicin. The mitochondrial localization of MRP-1 was examined in ES cell lines by differential centrifugation and membrane solubilization by digitonin. Whether MRP-1 is chaperoned by heat shock proteins (HSPs) was investigated by immunoprecipitation, immunofluorescence microscopy, and HSP knockout using small hairpin RNA and inhibitors (apoptozole, 17-AAG, and NVPAUY). The effect of disrupting mitochondrial MRP-1-dependent efflux activity on the cytotoxic effect of doxorubicin was investigated by counting viable cell number. Mitochondrial MRP-1 is glycosylated and localized to the outer mitochondrial membrane, where it is coexpressed with HSP90. MRP-1 binds to both HSP90 and HSP70, although only inhibition of HSP90β decreases expression of MRP-1 in the mitochondria. Disruption of mitochondrial MRP-1-dependent efflux significantly increases the cytotoxic effect of doxorubicin (combination index, <0.9). For the first time, we have demonstrated that mitochondrial MRP-1 is expressed in the outer mitochondrial membrane and is a client protein of HSP90β, where it may play a role in the doxorubicin-induced resistance of ES.-Roundhill, E., Turnbull, D., Burchill, S. Localization of MRP-1 to the outer mitochondrial membrane by the chaperone protein HSP90β.

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“…Hsp70 and Hsp40 also bind HSF1, but do not inhibit its transcriptional activity. Under stress, Hsp90 releases HSF1, which forms trimers, relocates to the nucleus, and induces the expression of HSPs (Morimoto 2008;Luo 2010Luo , 2013. Hsp90 inhibitors have been developed to reverse the permissive role of Hsp90 in tumorigenesis.…”

Section: Hsp90mentioning

confidence: 99%

Protein Quality Control in Brain Aging: Lessons from Protein Misfolding Disorders in Drosophila

2015

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Protein quality control is an essential process for cellular survival. When protein damage occurs, a series of coordinated response mechanisms repair or degrade damaged proteins to avoid the accumulation of toxic protein aggregates and restore proteostasis. However, the amount of misfolded proteins increases during aging overwhelming the mechanisms responsible for protein quality control, thus leading to the development of several age-dependent neurodegenerative disorders. Interestingly, targeted expression of proteins causative of these diseases in flies reproduces the pathological behaviors seen in humans. This remarkable conservation provides a valuable experimental tool to elucidate the complex mechanisms associated with the maintenance of proteostasis. In this chapter, we summarize how Drosophila has contributed to understand the roles of the heat shock response, the unfolded protein response, autophagy and the ubiquitin proteasome system in brain aging and neurodegeneration associated with proteinmisfolding disorders. In addition, we describe fundamental contributions of the fly system to the design of new therapeutic strategies for these devastating disorders.

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Heat Shock Protein 90-α Mediates Aldo-Keto Reductase 1B10 (AKR1B10) Protein Secretion through Secretory Lysosomes

Cited by 24 publications

References 37 publications

A Large‐Scale Multicenter Study Validates Aldo‐Keto Reductase Family 1 Member B10 as a Prevalent Serum Marker for Detection of Hepatocellular Carcinoma

A Large‐Scale Multicenter Study Validates Aldo‐Keto Reductase Family 1 Member B10 as a Prevalent Serum Marker for Detection of Hepatocellular Carcinoma

Localization of MRP‐1 to the outer mitochondrial membrane by the chaperone protein HSP90β

Protein Quality Control in Brain Aging: Lessons from Protein Misfolding Disorders in Drosophila

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