新型分泌蛋白AKR1B10的分泌机制及其在乳腺癌分子诊断中的应用研究
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摘要
醛酮还原酶家族1成员B10(Aldo-keto Reductase family 1, member B10, AKR1B10),也叫醛糖还原酶相似蛋白1 (Aldo-keto Reductase Like-Protein, ARL-1)主要表达于正常人的结肠和小肠组织,而在肝、胸腺、前列腺、睾丸和骨骼肌等组织中表达低。AKR1B1O一方面还原醛酮类羰基化合物为相应的醇类,保护DNA免于羰基毒性损伤和细胞免于癌变；另一方面AKR1B10稳定乙酰辅酶A羧化酶α(Acetyl-CoA Carboxylase, ACCα),阻止ACCα降解,从而调节脂质合成,促进肿瘤细胞生长增值。因此,AKR1B10与肿瘤的发生发展密切相关。AKR1B10在肝癌、肺癌、子宫颈癌等多种肿瘤细胞中高表达,是吸烟导致的非小细胞型肺癌的病理学诊断标记物。
在本课题中,利用自行开发的ELISA检测法(.已申请专利保护：US13/017,618),我们发现AKR1B10可从肿瘤细胞内分泌到细胞外。这种分泌现象不但发生在肠癌细胞株HCT-8、HT29,肺癌细胞株H460、A549,乳腺癌细胞株MDA-MB-468, BT-20,肝癌细胞株HepG2等表达内源性AKR1B0的肿瘤细胞株和转染外源性AKR1B10基因的MCF-7乳腺癌细胞株。血清可刺激细胞分泌AKR1B10,而且与透析过的血清相比,平台期的高度无明显变化,但达到平台期的时间更短；这提示血清小分子(离子)决定了分泌的速度,而血清大分子决定了分泌的峰值。AKR1B10的分泌量与细胞数目正相关,但单位细胞分泌量与细胞密度负相关。分泌的AKR1B10仍然保留着与等量纯蛋白酶同样的活性。
本课题还深入研究了AKRlB10分泌的机制。通过信号肽分析软件,我们发现AKR1B10的氨基酸序列缺少分泌信号肽,所以推测AKR1B10并不能通过经典的内质网-高尔基(ER-to-Golgi)分泌途径分泌到细胞外的。AKR1B10的分泌不受蛋白翻译抑制剂Cycloheximide(CHX)和ER-to-Golgi分泌途径抑制剂Brefeldin A的影响,说明分泌的AKR1B10是已经合成的,而与正在翻译合成的AKRlB10无关,也与ER到Golgi体之间的转运无关。因此,AKR1B10的分泌途径是非ER-to-Golgi依赖的非经典途径。
溶酶体介导的分泌途径是常见的非经典分泌途径。为了论证AKR1B10是否也是通过溶酶体途径分泌的,我们分离了HCT-8细胞的溶酶体,发现AKR1B10存在溶酶体中；用荧光蛋白保护分析法发现,细胞被打孔剂Digitonin和胰蛋白酶(Trypsin)处理后,胞浆内绝大部分带绿色荧光(EGFP)标记的游离AKR1B10被消化掉了,而剩下的点状EGFP-AKR1B10可与溶酶体共定位。这说明AKR1B10存在于溶酶体。为了进一步论证AKR1B10的分泌与分泌型溶酶体出胞的关系,我们用影响溶酶体出胞的因素如温度、ATP、钙离子(Ca2+)等处理HCT-8细胞,发现温度越高,AKR1B10分泌越多,温度越低,分泌越少,4℃时,分泌几乎停止；提供能量的ATP能促进AKR1B10分泌；增加培养基中Ca2+浓度也可促进AKR1B10的分泌,Ca2+跨膜转运体Ionomycin则显著地促进了AKR1B10的释放。趋溶酶体药氯化氨(NH4C1)一方面可促进溶酶体出胞,另一方面可阻止蛋白进入溶酶体；因此,用N-H4C1预处理HCT-8细胞后,AKR1B10分泌减少了；而未预处理组,NH4Cl促进了AKR1B10的分泌。同时,我们发现AKR1B10的释放与溶酶体标记物Cathepsin D的释放规律是一致的,这提示AKR1B10是通过溶酶体介导的非经典途径分泌的。分泌性溶酶体的出胞受调节细胞内Ca2+浓度的信号通路所调节。AKR1B10的分泌受到这些通路中关键信号分子ADP核糖基化因子(ADP-ribosylation factor, ARF)抑制剂Exo-1、磷脂酶C(phospholipase C, PLC)抑制剂U73122的抑制,受G蛋白激动剂GTPγS、G蛋白偶联受体配体fMLP的刺激。进一步证明了AKR1B10的分泌是通过分泌性溶酶体的出胞介导的。
本课题接着探讨了AKR1B10进入溶酶体的机制。我们用ATP结合盒超家族转运蛋白(ATP-Binding cassette, ABC)的抑制剂4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS)和Glibenclamide(Glib)处理HCT-8细胞后,发现溶酶体内AKR1B10含量显著减少,分泌到细胞外的AKR1B10也相应减少。提示溶酶体膜上ABC转运体是转运AKR1B10进入溶酶体的主要通道。
本课题还证实了AKR1B10在体内也是分泌蛋白。因为AKR1B10主要表达于肠道上皮,因此我们收集了11例正常人的回肠液,检测了其中AKR1B10浓度,发现AKR1B10特异性表达于成熟的肠道上皮细胞,并分泌到肠腔,浓度为188.6～535.7ng/ml (average=298.1ng/ml, n=11)。
本课题进一步探讨了主要分布于胞浆的AKR1B10转运到溶酶体的机制。用免疫共沉淀(CoIP)和Pulldown法发现热休克蛋白90a(Heat Shock Protein 90 alpha, HSP90a)可与AKR1B10相互作用。HSP90α抑制剂Geldanamycin (GA)显著地抑制了HCT-8细胞AKR1B10的分泌,降低了HSP90α与AKR1B1O的结合,减少了AKRlB10在溶酶体内的聚集。
非经典分泌蛋白通常包含一个与分泌相关的功能域。因此,我们研究了不同AKR1B10肽段的分泌效率,以及它们与HSP90α的结合情况。通过构建AKR1B10全长和不同肽段(N端的N1-39、N1-83、N1-142、N1-231以及C端的C204-261、C204-316)的表达载体GST/pGEX,并将它们分别转染到293T细胞中；与全长AKR1B10的分泌效率相比,N端肽段(N1-231)不具有分泌功能；而C端肽段C204-261、C204-316的相对分泌效率可达74.2±3.0%和81.54±5.5%。这提示介导AKR1B10分泌的功能域可能存在于C端肽段C204-261。接着,我们将螺旋10(氨基酸残基233到240)上氨基酸残基233K、236E和240K三个位点进行了单点或联合突变；与野生型AKR1B10相比,233K/A、236E/A和240K/A单点突变型AKR1B10的分泌效率分别下降到59.2±2.1%、63.3±1.1%和46.9±3.1%；而两点联合突变型AKR1B10的分泌效率减少到了43.15±1.5%(K233A和E236A联合突变)、33.30±1%(K233A和K240A联合突变)和33.52±3.1%(E236A和K240A联合突变)；三点突变型AKR1B10的分泌效率只有野生型的18.24±3.2%。免疫共沉淀实验显示,三点突变性AKR1B10丧失了结合HSP90α的能力；western blot分析表明,突变性AKR1B10在溶酶体内的聚集显著减少了。这些结果提示,螺旋10(aa233-240)通过与HSP90α结合从而介导了AKR1B10的分泌；该螺旋中氨基酸位点233K、236E和240K是结合HSP90α的关键位点。
最近,我们研究发现,AKR1B10在乳腺癌组织中过表达,可增加乳腺癌细胞的脂质合成,促进生长增值,抑制醛酮类羰基化合物诱导的凋亡；AKR1B10高表达与乳腺癌的生长、淋巴结转移和存活率相关,提示AKR1B10是一个新的乳腺癌预测指标。因此,本课题探讨了开发AKR1B10为诊断乳腺癌的血清学指标的可行性。通过对乳腺癌组织芯片进行免疫染色发现,正常乳腺小叶和乳腺管低表达或不表达AKR1B10；而在28例原位乳腺管癌中,有20例(71.4%)AKR1B10高表达；在220例乳腺浸润癌中有184(83.6%)AKR1B10高表达；在32例术后复发乳腺癌中有28例AKR1B10高表达。此外,我们检测了50例乳腺癌患者肿瘤组织中AKR1B10的表达和血液中AKR1B10的含量,发现48例乳腺癌组织中的AKR1B10表达水平要显著高于癌旁正常组织的；血清中AKR1B10的平均浓度为20.72ng/ml,显著高于正常人群的5.19ng/ml；乳腺癌患者血清AKR1B10的浓度与肿瘤组织中AKR1B10的表达水平呈正相关。提示AKR1B10可作为诊断乳腺癌的血清分子标记物。
总之,AKR1B10可通过HSP90α介导的溶酶体途径分泌到细胞外；AKR1B10可开发为诊断乳腺癌的血清学标记物。
Aldo-keto reductase family 1 member B10 (AKR1B10) is primarily expressed in the normal human colon and small intestine. AKR1B10 efficiently catalyzes the reduction of aldehydes and ketones to form corresponding alcohols to protect cells from carbonyls-induced DNA damage and carcinogenesis. Our previous studies have shown that AKR1B10 mediates the ubiquitin-dependent degradation of acetyl-CoA carboxylase-a (ACCa). ACCa is a rate-limiting enzyme in long chain fatty acid synthesis. Therefore, AKR1B10 plays important roles in lipid synthesis, cell growth and proliferation. Futhermore, AKR1B10 is also highly related to tumorigenesis since it is overexpressed in liver, lung, cervices cancers.
In this study, we developed a novel AKR1B10 detection ELISA kit, with purified AKR1B10 as standard samples and found not only that endogenous AKR1B10 is secreted from colon cancer cell lines HCT8, HT29, breat cancer cell lines H460, A549, MDA-MB-468, hepatic cancer cell line HepG2, but also exogenous AKR1B10 from 293T transfected with AKR1B10 gene. AKR1B10's secretion was stimulated by serum and decreased in serum-free or low serum conditions. Serum dialyzed with 5.0 kDa cut-off filters had less stimulatory activity at beginning, but the same plateau was eventually reached, suggesting that certain small molecules (such as ions) in serum were responsible for the immediate early stimulation, and large molecules (>5.0 kDa) participated in the later phase of stimulation. Cell number positively and cell density negatively affected AKR1B10's secretion. AKR1B10 is secreted in a functional form, which is identified by enzymatic activity assay to DL-glyceraldehyde.
The potential mechanisms of AKR1B10 secretion were subsequently explored in current study. We found that AKRIBIO lacks a secretion signal peptide in its amino acid sequence by signal peptide prediction analysis. At the same time, AKR1B10's secretion was not affected by the protein synthesis inhibitor cycloheximide and the classical protein secretion pathway inhibitor brefeldin A. Therefore AKRIBIO is released through an endoplasmic reticulum (ER)-to-Golgi-independent non-classical secretion pathway.
Lysosome-mediated protein secretion is one of most important non-classical secretion pathways. We isolated lysosomes and found AKR1B10 located in lysosomal fraction with Cathepsin D and protected from protease digestion. Fluorescence protein protection assay showed that EGFP-AKR1B10 was located in lysosomes marked with LysoTracker(?)Red DND-99, and this location can protect AKRIBIO from protease digestion by exogenous trypsin. AKR1B10's secretion is stimulated by many factors of stimulating lysosome exocytosis such as temperature, ATP, Ca2+and Ca2+carrier ionomycin, Mg2+chelator EDTA. Lysosomotropic NH4Cl induced AKR1B10 accumulation in lysosome and lysosome exocytosis to increase AKR1B10 release. Lysosomal exocytosis is regulated by several signal pathways modulating intracellular Ca2+ concentration, such as ADP-ribosylation factor (ARF), phospholipase C (PLC) and G-protein. AKR1B10 secretion is inhibited by Exo-1, an ARF inhibitor, and U73122, a PLC inhibitor, but stimulated by GTPyS, an activator of G-protein, and fMLP, a ligand of G-protein coupling receptor, suggesting AKR1B10 secretion is modulated by the signal pathways regulating secretory lysosomes exocytosis. AKR1B10 is secreted together with Cathepsin D, a lysosomal marker. Therefore, AKR1B10 is secreted through lysosome-mediated non-classical pathway. We also determined the translocation of AKR1B10 into lysosomes. ABC transporter inhibitors Glib and DIDS suppressed AKR1B10 secretion by reducing its accumulation in lysosomes, suggesting the role of ABC transporters in the entry of AKR1B10 into lysosomes.
In this study, we also identify AKR1B10 as a secretory protein in vivo. AKR1B10 is primarily expressed in the normal human colon and small intestine, so we detected AKR1B10 concentration in ileal fluid from normal subjects, and found that in the intestine, AKR1B10 is specifically expressed in mature epithelial cells and secreted into the ileal fluids of lumen at the concentration of 188.6～535.7ng/ml (average= 298.1 ng/ml, n=11). Then we further explored the mechanism on the transportation of AKR1B10 to lysosome. HSP90a, a chaperone molecular, plays an important role in protein folding, transportation. We found that cytosolic AKR1B10 interacts with HSP90a by immunoprecipitation and pulldown assays. Geldamycin (GA), a HSP90a-specific inhibitor, decreased AKR1B10 accumulation in lysosomes and AKR1B10 secretion. Therefore HSP90a transports AKR1B10 to lysosomes.
A functional domain is often recognized in the proteins secreted through a nonclassical secretion pathway. We tested the secretory activity of different N-and C-terminal peptides. GST-tagged N/C-terminal peptides were expressed in 293T cells and tested for their secretory activity. The N-terminus up to 231aa had not secretory activity, whereas C-terminal peptides (C204-261 and C204-316) were secreted with efficiencies of 74.2±3.0%and 81.5±5.5% compared to full length AKR1B10 (316aa), suggesting that the functional domain mediating AKR1B10 secretion may be located in the C-terminal peptide C204-261. We replaced the amino acids with a long, charged residue in helix 10 (233-240aa) with alanine, producing mutants K233A, E236A, or K240A. A single mutation of K233A, E236A, or K240A decreased secretory efficiency of AKR1B10 to 59.2±2.1%,63.3±1.1%, and 46.9±3.1%, respectively. Combinations of two-site mutations further reduced the secretory activity to 43.15±1.5% for K233A plus E236A,33.3O±1% for K233A plus K240A, and 33.52±3.1% for E236A plus K240A, and all three-site mutations lowered down AKR1B10 secretory activity to 18.2±3.2%. These secretory data were supported by the decrease of the mutant AKR1B10 in lysosome. The mutant AKR1B10 in lost the capability of interacting with HSP90. These data suggest that the helix 10 acts as a functional domain for the secretion of AKR1B10 and the amino acids K233, E236, and K240 in this helix are the key residues.
Recently, my colleagues found that overexpression of AKR1B10 in breast cancer is associated with tumor growth, lymph node metastasis, and patient survival, suggesting that AKR1B10 may promote tumor growth and progression, thus being a novel prognostic marker. In this study, we detected AKR1B10 expression in tissue microarray of breast cancer by immunohistochemistry and found AKR1B10 was undetectable or at a very low level in normal breast lobules and ducts, but overexpressed in 20 of 28 (71.4%) ductal carcinomas in situ,184 of 220 (83.6%) infiltrating carcinomas, and 28 of 32 (87.5%) recurrent tumors. Moreover, we collected 50 cases of tumor tissue and blood samples of breast cancer patients and found that AKRIB10 was highly expressed in tumor tissue than adjacent noncancerous tissue in 48 cases, and the AKRIB10 concentration was 20.72 ng/ml, which was the higher than the concentration of 5.19 ng/ml in normal subjects. There is a positive correlation between AKR1B10 concentration in serum and AKR1B10 expression in tissue of the breast cancer of patients, suggesting that AKR1B10 may be a novel serum marker for breast cancer.
In summary, this study demonstrated that AKR1B10 is secreted through a HSP90a-mediated lysosomal nonclassical pathway and may act as a serum biomarker for the diagnosis of breast cancer.
在本课题中,利用自行开发的ELISA检测法(.已申请专利保护：US13/017,618),我们发现AKR1B10可从肿瘤细胞内分泌到细胞外。这种分泌现象不但发生在肠癌细胞株HCT-8、HT29,肺癌细胞株H460、A549,乳腺癌细胞株MDA-MB-468, BT-20,肝癌细胞株HepG2等表达内源性AKR1B0的肿瘤细胞株和转染外源性AKR1B10基因的MCF-7乳腺癌细胞株。血清可刺激细胞分泌AKR1B10,而且与透析过的血清相比,平台期的高度无明显变化,但达到平台期的时间更短；这提示血清小分子(离子)决定了分泌的速度,而血清大分子决定了分泌的峰值。AKR1B10的分泌量与细胞数目正相关,但单位细胞分泌量与细胞密度负相关。分泌的AKR1B10仍然保留着与等量纯蛋白酶同样的活性。
本课题还深入研究了AKRlB10分泌的机制。通过信号肽分析软件,我们发现AKR1B10的氨基酸序列缺少分泌信号肽,所以推测AKR1B10并不能通过经典的内质网-高尔基(ER-to-Golgi)分泌途径分泌到细胞外的。AKR1B10的分泌不受蛋白翻译抑制剂Cycloheximide(CHX)和ER-to-Golgi分泌途径抑制剂Brefeldin A的影响,说明分泌的AKR1B10是已经合成的,而与正在翻译合成的AKRlB10无关,也与ER到Golgi体之间的转运无关。因此,AKR1B10的分泌途径是非ER-to-Golgi依赖的非经典途径。
溶酶体介导的分泌途径是常见的非经典分泌途径。为了论证AKR1B10是否也是通过溶酶体途径分泌的,我们分离了HCT-8细胞的溶酶体,发现AKR1B10存在溶酶体中；用荧光蛋白保护分析法发现,细胞被打孔剂Digitonin和胰蛋白酶(Trypsin)处理后,胞浆内绝大部分带绿色荧光(EGFP)标记的游离AKR1B10被消化掉了,而剩下的点状EGFP-AKR1B10可与溶酶体共定位。这说明AKR1B10存在于溶酶体。为了进一步论证AKR1B10的分泌与分泌型溶酶体出胞的关系,我们用影响溶酶体出胞的因素如温度、ATP、钙离子(Ca2+)等处理HCT-8细胞,发现温度越高,AKR1B10分泌越多,温度越低,分泌越少,4℃时,分泌几乎停止；提供能量的ATP能促进AKR1B10分泌；增加培养基中Ca2+浓度也可促进AKR1B10的分泌,Ca2+跨膜转运体Ionomycin则显著地促进了AKR1B10的释放。趋溶酶体药氯化氨(NH4C1)一方面可促进溶酶体出胞,另一方面可阻止蛋白进入溶酶体；因此,用N-H4C1预处理HCT-8细胞后,AKR1B10分泌减少了；而未预处理组,NH4Cl促进了AKR1B10的分泌。同时,我们发现AKR1B10的释放与溶酶体标记物Cathepsin D的释放规律是一致的,这提示AKR1B10是通过溶酶体介导的非经典途径分泌的。分泌性溶酶体的出胞受调节细胞内Ca2+浓度的信号通路所调节。AKR1B10的分泌受到这些通路中关键信号分子ADP核糖基化因子(ADP-ribosylation factor, ARF)抑制剂Exo-1、磷脂酶C(phospholipase C, PLC)抑制剂U73122的抑制,受G蛋白激动剂GTPγS、G蛋白偶联受体配体fMLP的刺激。进一步证明了AKR1B10的分泌是通过分泌性溶酶体的出胞介导的。
本课题接着探讨了AKR1B10进入溶酶体的机制。我们用ATP结合盒超家族转运蛋白(ATP-Binding cassette, ABC)的抑制剂4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS)和Glibenclamide(Glib)处理HCT-8细胞后,发现溶酶体内AKR1B10含量显著减少,分泌到细胞外的AKR1B10也相应减少。提示溶酶体膜上ABC转运体是转运AKR1B10进入溶酶体的主要通道。
本课题还证实了AKR1B10在体内也是分泌蛋白。因为AKR1B10主要表达于肠道上皮,因此我们收集了11例正常人的回肠液,检测了其中AKR1B10浓度,发现AKR1B10特异性表达于成熟的肠道上皮细胞,并分泌到肠腔,浓度为188.6～535.7ng/ml (average=298.1ng/ml, n=11)。
本课题进一步探讨了主要分布于胞浆的AKR1B10转运到溶酶体的机制。用免疫共沉淀(CoIP)和Pulldown法发现热休克蛋白90a(Heat Shock Protein 90 alpha, HSP90a)可与AKR1B10相互作用。HSP90α抑制剂Geldanamycin (GA)显著地抑制了HCT-8细胞AKR1B10的分泌,降低了HSP90α与AKR1B1O的结合,减少了AKRlB10在溶酶体内的聚集。
非经典分泌蛋白通常包含一个与分泌相关的功能域。因此,我们研究了不同AKR1B10肽段的分泌效率,以及它们与HSP90α的结合情况。通过构建AKR1B10全长和不同肽段(N端的N1-39、N1-83、N1-142、N1-231以及C端的C204-261、C204-316)的表达载体GST/pGEX,并将它们分别转染到293T细胞中；与全长AKR1B10的分泌效率相比,N端肽段(N1-231)不具有分泌功能；而C端肽段C204-261、C204-316的相对分泌效率可达74.2±3.0%和81.54±5.5%。这提示介导AKR1B10分泌的功能域可能存在于C端肽段C204-261。接着,我们将螺旋10(氨基酸残基233到240)上氨基酸残基233K、236E和240K三个位点进行了单点或联合突变；与野生型AKR1B10相比,233K/A、236E/A和240K/A单点突变型AKR1B10的分泌效率分别下降到59.2±2.1%、63.3±1.1%和46.9±3.1%；而两点联合突变型AKR1B10的分泌效率减少到了43.15±1.5%(K233A和E236A联合突变)、33.30±1%(K233A和K240A联合突变)和33.52±3.1%(E236A和K240A联合突变)；三点突变型AKR1B10的分泌效率只有野生型的18.24±3.2%。免疫共沉淀实验显示,三点突变性AKR1B10丧失了结合HSP90α的能力；western blot分析表明,突变性AKR1B10在溶酶体内的聚集显著减少了。这些结果提示,螺旋10(aa233-240)通过与HSP90α结合从而介导了AKR1B10的分泌；该螺旋中氨基酸位点233K、236E和240K是结合HSP90α的关键位点。
最近,我们研究发现,AKR1B10在乳腺癌组织中过表达,可增加乳腺癌细胞的脂质合成,促进生长增值,抑制醛酮类羰基化合物诱导的凋亡；AKR1B10高表达与乳腺癌的生长、淋巴结转移和存活率相关,提示AKR1B10是一个新的乳腺癌预测指标。因此,本课题探讨了开发AKR1B10为诊断乳腺癌的血清学指标的可行性。通过对乳腺癌组织芯片进行免疫染色发现,正常乳腺小叶和乳腺管低表达或不表达AKR1B10；而在28例原位乳腺管癌中,有20例(71.4%)AKR1B10高表达；在220例乳腺浸润癌中有184(83.6%)AKR1B10高表达；在32例术后复发乳腺癌中有28例AKR1B10高表达。此外,我们检测了50例乳腺癌患者肿瘤组织中AKR1B10的表达和血液中AKR1B10的含量,发现48例乳腺癌组织中的AKR1B10表达水平要显著高于癌旁正常组织的；血清中AKR1B10的平均浓度为20.72ng/ml,显著高于正常人群的5.19ng/ml；乳腺癌患者血清AKR1B10的浓度与肿瘤组织中AKR1B10的表达水平呈正相关。提示AKR1B10可作为诊断乳腺癌的血清分子标记物。
总之,AKR1B10可通过HSP90α介导的溶酶体途径分泌到细胞外；AKR1B10可开发为诊断乳腺癌的血清学标记物。
Aldo-keto reductase family 1 member B10 (AKR1B10) is primarily expressed in the normal human colon and small intestine. AKR1B10 efficiently catalyzes the reduction of aldehydes and ketones to form corresponding alcohols to protect cells from carbonyls-induced DNA damage and carcinogenesis. Our previous studies have shown that AKR1B10 mediates the ubiquitin-dependent degradation of acetyl-CoA carboxylase-a (ACCa). ACCa is a rate-limiting enzyme in long chain fatty acid synthesis. Therefore, AKR1B10 plays important roles in lipid synthesis, cell growth and proliferation. Futhermore, AKR1B10 is also highly related to tumorigenesis since it is overexpressed in liver, lung, cervices cancers.
In this study, we developed a novel AKR1B10 detection ELISA kit, with purified AKR1B10 as standard samples and found not only that endogenous AKR1B10 is secreted from colon cancer cell lines HCT8, HT29, breat cancer cell lines H460, A549, MDA-MB-468, hepatic cancer cell line HepG2, but also exogenous AKR1B10 from 293T transfected with AKR1B10 gene. AKR1B10's secretion was stimulated by serum and decreased in serum-free or low serum conditions. Serum dialyzed with 5.0 kDa cut-off filters had less stimulatory activity at beginning, but the same plateau was eventually reached, suggesting that certain small molecules (such as ions) in serum were responsible for the immediate early stimulation, and large molecules (>5.0 kDa) participated in the later phase of stimulation. Cell number positively and cell density negatively affected AKR1B10's secretion. AKR1B10 is secreted in a functional form, which is identified by enzymatic activity assay to DL-glyceraldehyde.
The potential mechanisms of AKR1B10 secretion were subsequently explored in current study. We found that AKRIBIO lacks a secretion signal peptide in its amino acid sequence by signal peptide prediction analysis. At the same time, AKR1B10's secretion was not affected by the protein synthesis inhibitor cycloheximide and the classical protein secretion pathway inhibitor brefeldin A. Therefore AKRIBIO is released through an endoplasmic reticulum (ER)-to-Golgi-independent non-classical secretion pathway.
Lysosome-mediated protein secretion is one of most important non-classical secretion pathways. We isolated lysosomes and found AKR1B10 located in lysosomal fraction with Cathepsin D and protected from protease digestion. Fluorescence protein protection assay showed that EGFP-AKR1B10 was located in lysosomes marked with LysoTracker(?)Red DND-99, and this location can protect AKRIBIO from protease digestion by exogenous trypsin. AKR1B10's secretion is stimulated by many factors of stimulating lysosome exocytosis such as temperature, ATP, Ca2+and Ca2+carrier ionomycin, Mg2+chelator EDTA. Lysosomotropic NH4Cl induced AKR1B10 accumulation in lysosome and lysosome exocytosis to increase AKR1B10 release. Lysosomal exocytosis is regulated by several signal pathways modulating intracellular Ca2+ concentration, such as ADP-ribosylation factor (ARF), phospholipase C (PLC) and G-protein. AKR1B10 secretion is inhibited by Exo-1, an ARF inhibitor, and U73122, a PLC inhibitor, but stimulated by GTPyS, an activator of G-protein, and fMLP, a ligand of G-protein coupling receptor, suggesting AKR1B10 secretion is modulated by the signal pathways regulating secretory lysosomes exocytosis. AKR1B10 is secreted together with Cathepsin D, a lysosomal marker. Therefore, AKR1B10 is secreted through lysosome-mediated non-classical pathway. We also determined the translocation of AKR1B10 into lysosomes. ABC transporter inhibitors Glib and DIDS suppressed AKR1B10 secretion by reducing its accumulation in lysosomes, suggesting the role of ABC transporters in the entry of AKR1B10 into lysosomes.
In this study, we also identify AKR1B10 as a secretory protein in vivo. AKR1B10 is primarily expressed in the normal human colon and small intestine, so we detected AKR1B10 concentration in ileal fluid from normal subjects, and found that in the intestine, AKR1B10 is specifically expressed in mature epithelial cells and secreted into the ileal fluids of lumen at the concentration of 188.6～535.7ng/ml (average= 298.1 ng/ml, n=11). Then we further explored the mechanism on the transportation of AKR1B10 to lysosome. HSP90a, a chaperone molecular, plays an important role in protein folding, transportation. We found that cytosolic AKR1B10 interacts with HSP90a by immunoprecipitation and pulldown assays. Geldamycin (GA), a HSP90a-specific inhibitor, decreased AKR1B10 accumulation in lysosomes and AKR1B10 secretion. Therefore HSP90a transports AKR1B10 to lysosomes.
A functional domain is often recognized in the proteins secreted through a nonclassical secretion pathway. We tested the secretory activity of different N-and C-terminal peptides. GST-tagged N/C-terminal peptides were expressed in 293T cells and tested for their secretory activity. The N-terminus up to 231aa had not secretory activity, whereas C-terminal peptides (C204-261 and C204-316) were secreted with efficiencies of 74.2±3.0%and 81.5±5.5% compared to full length AKR1B10 (316aa), suggesting that the functional domain mediating AKR1B10 secretion may be located in the C-terminal peptide C204-261. We replaced the amino acids with a long, charged residue in helix 10 (233-240aa) with alanine, producing mutants K233A, E236A, or K240A. A single mutation of K233A, E236A, or K240A decreased secretory efficiency of AKR1B10 to 59.2±2.1%,63.3±1.1%, and 46.9±3.1%, respectively. Combinations of two-site mutations further reduced the secretory activity to 43.15±1.5% for K233A plus E236A,33.3O±1% for K233A plus K240A, and 33.52±3.1% for E236A plus K240A, and all three-site mutations lowered down AKR1B10 secretory activity to 18.2±3.2%. These secretory data were supported by the decrease of the mutant AKR1B10 in lysosome. The mutant AKR1B10 in lost the capability of interacting with HSP90. These data suggest that the helix 10 acts as a functional domain for the secretion of AKR1B10 and the amino acids K233, E236, and K240 in this helix are the key residues.
Recently, my colleagues found that overexpression of AKR1B10 in breast cancer is associated with tumor growth, lymph node metastasis, and patient survival, suggesting that AKR1B10 may promote tumor growth and progression, thus being a novel prognostic marker. In this study, we detected AKR1B10 expression in tissue microarray of breast cancer by immunohistochemistry and found AKR1B10 was undetectable or at a very low level in normal breast lobules and ducts, but overexpressed in 20 of 28 (71.4%) ductal carcinomas in situ,184 of 220 (83.6%) infiltrating carcinomas, and 28 of 32 (87.5%) recurrent tumors. Moreover, we collected 50 cases of tumor tissue and blood samples of breast cancer patients and found that AKRIB10 was highly expressed in tumor tissue than adjacent noncancerous tissue in 48 cases, and the AKRIB10 concentration was 20.72 ng/ml, which was the higher than the concentration of 5.19 ng/ml in normal subjects. There is a positive correlation between AKR1B10 concentration in serum and AKR1B10 expression in tissue of the breast cancer of patients, suggesting that AKR1B10 may be a novel serum marker for breast cancer.
In summary, this study demonstrated that AKR1B10 is secreted through a HSP90a-mediated lysosomal nonclassical pathway and may act as a serum biomarker for the diagnosis of breast cancer.
引文
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