白血病细胞多药耐药性的诱导及对三氧化二砷敏感性的细胞分子机制研究
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摘要
白血病获得性多药耐药(multidrug resistance, MDR)现象是白血病治疗领域尚未解决的难题和主要的关键难点之一。尽管长期以来围绕白血病耐药性的发生机制、调控通路以及干预措施诸方面进行了大量的探索性研究,但迄今为止尚没有对白血病细胞耐药性的发生和调控机制得到清晰的认识,也无有效且临床实用的干预对策。近年来有关白血病干细胞(leukemia stem cells, LSC)在白血病多药耐药性中的关键作用受到关注,推测LSC可能是白血病药物耐受性的核心和白血病常规治疗失败、复发的根源。因此,研究白血病细胞的耐药特性及细胞分子机制,有针对性地探寻干预白血病耐药性的药物或策略,以期可为临床耐药性白血病的治疗提供新的潜在靶点。
我们采用阿霉素(Adriamycin, ADM)模拟体内化疗过程,逐步提高药物浓度、长期、间歇性刺激的方法诱导人白血病HL-60细胞获得耐药特性,建立稳定的白血病多药耐药细胞株(HL-60/R),并动态观察白血病细胞获得耐药性的过程中药物敏感性、耐药基因／蛋白表达及功能、蛋白质组、LSC含量等的变化。研究发现,历经22个月的ADM诱导后,耐药性的HL-60/R细胞对ADM的耐受性增高85.68倍,且与顺铂、长春新碱、依托泊苷、阿糖胞苷和柔红霉素等多种化疗药物交叉耐受。HL-60/R细胞在无ADM条件下培养3个月以上或冻存-重新复苏其耐药性均无降低,证明该细胞具备稳定的多药耐药性。动态观察显示,HL-60/R细胞在生长速度、细胞形态以及细胞周期分布等方面均与亲本HL-60细胞有不同程度的差异；随诱导时间延长和诱导药物浓度提高,药物转运蛋白ABCC1/MRP1、 ABCB1/P-gp和ABCG2/BCRP的表达逐步增高,尤以mdrl/P-gp为著,且诱导耐药细胞对ADM或rhodamine123(Rhl23)的蓄积明显减少、外排显著增加。蛋白质表达谱(蛋白质组)初步揭示HL-60/R细胞存在大量的差异表达蛋白,有待进一步的质谱鉴定分析。ADM诱导过程中HL-60细胞群体中表面标志为CD34+CD38-CD123+的的LSC的含量同步增高且HL-60/R细胞较亲本HL-60细胞具有显著增强的集落形成能力。ADM诱导后的HL-60细胞在无ADM培养基中随着扩增培养时间延长,细胞群体中LSC的比例逐渐降低,稳定在10%左右,ADM重新诱导复又增高。提示在ADM的长期反复诱导过程中HL-60细胞群体中的LSC因其天然耐药性而存活下来,并可能因药物的反复诱导而获得高耐药特性和独特调控通路,成为耐药性白血病细胞群体的源泉。有趣的是,不同于其它已知的多药耐药性白血病细胞,我们诱导建立的HL-60/R对三氧化二砷(arsenic trioxide, AS2O3)具有很强的交叉耐受性。
As203因具有显著疗效且与常规抗肿瘤药物无交叉耐药性而被广泛用于白血病及实体肿瘤的治疗,取得显著的疗效。研究证实大多数MDR白血病细胞并不对As203产生交叉耐药性,甚至具有更高的敏感性,可能与As203并非P-gp的底物且能抑制P-gp活性有关,同时,细胞的抗砷性与MPR1、MPR2和ASNA1等转运蛋白对砷的转运密切相关。我们采用ADM诱导的mdr1/P-gp高表达的HL-60/R耐药细胞对As203高度耐受,但同样是ADM诱导和mdr1/P-gp高表达的K562/ADM耐药细胞却对As203具有高敏感性。为探讨白血病MDR细胞对As203耐受还是敏感的分子机制,我们对比观察了对K562/ADM细胞、HL-60/R细胞及其亲本药物敏感的K562细胞和HL-60细胞砷转运相关蛋白的表达,以及与对As203敏感性的相关性。结果揭示，与亲本K562细胞和HL-60细胞相比较,K562/ADM细胞具有较低的MRP1、MRP2和ASNA1的表达,而HL-60/R细胞则表达更高,且明显高于K562/ADM细胞。As203促进HL-60/R细胞MRP1、MRP2和ASNA1的表达,却对K562/ADM细胞的表达具有不同程度的抑制作用。我们的研究首次证实对常规抗肿瘤药物抵抗的白血病耐药细胞是否与As203交叉耐受,主要与耐药细胞MPR1、 MPR2和ASNA1等砷转运相关蛋白的表达水平,以及As203作用对这些转运蛋白表达的影响密切相关。
我们的研究证实As203对白血病K562/ADM耐药细胞具有较高的凋亡诱导效应,且可明显提高内质网分子伴侣GRP78/Bip的表达。为探讨除As203抑制ABC转运蛋白表达外,内质网应激(endoplasmic reticulum stress, ERS)反应是否参与K562/ADM细胞对As203诱导凋亡敏感性的机制,我们进一步比较研究了As203诱导K562/ADM细胞及其亲本K562细胞凋亡过程中GRP78、CHOP/GADD153、 XBP1和caspase-12等内质网应激相关基因/蛋白和rndr1/P-gp、Bcl-2等耐药相关基因/蛋白的表达改变,以及Ca2+信号变化。研究结果证实As203可激活内质网应激反应的信号通路而诱发K562/ADM细胞和K562细胞发生内质网应激反应,并通过下调mdr1/P-gp表达增强未折叠蛋白反应(unfolded protein response, UPR)触发caspase依赖的细胞凋亡途径,下调Bcl-2促进Ca2+释放而启动内质网应激性凋的钙离子起始信号,诱导耐药性白血病K562/ADM细胞发生更强的内质网应激反应性细胞凋亡。
综上所述,采用ADM长期、反复、间歇性地提高药物浓度诱导白血病HL-60细胞(HL-60/R)获得了稳定的多药耐药特性,并具备高表达耐药相关基因/蛋白、蛋白质表达谱改变和LSC含量增高等特性,且与经典白血病MDR细胞不同,HL-60/R细胞具有对As203高耐受性的独特特性。ADM诱导耐药性的源泉可能为长期反复诱导过程中HL-60细胞群体中存活的耐药性LSC, LSC可能会因反复暴露于药物而发生适应性突变获得高耐药特性或独特调控信号通路,并传递给其后代细胞而形成耐药性白血病细胞群体。As203因与常规抗肿瘤药物无交叉耐药性而被用于耐药性白血病的治疗,但耐药性白血病细胞是否与As203交叉耐受,与其MPR1、MPR2和ASNA1等砷转运相关蛋白的表达及As203对转运蛋白表达的影响密切相关。As203激发内质网应激反应,并通过下调1ndr1/P-gp表达增强UPR触发caspase依赖的细胞死亡通路和下调Bcl-2促进Ca2+释放而启动内质网应激性细胞凋亡的钙离子起始信号,是其诱发某些耐药性白血病细胞如K562/ADM细胞更强凋亡效应的主要细胞分子机制。
The phenomenon of acquired multi-drug resistance (MDR) in leukemia is one of the major and pivotal impediments in leukemia therapy which has not yet been overcome. Over many years, a large number of extensive studies around leukemia drug-resistance, regulatory pathways and intervention measures have been launched but so far, the mechanisms remain incompletely understood and few effective or clinically practical countermeasures have been identified.Recently, the cardinal role of leukemia stem cells (LSC) in leukemia-MDR has attracted widespread attention and it has been speculated that they are the core factor underlying leukemia drug resistance and also the key cause of conventional chemotherapy failure and relapse in leukemia. Therefore, it is necessary to study the resistance characteristics of leukemia and its cellular and molecular mechanisms and to specifically explore ways to overcome these to provide new potential targets for clinical treatment of drug-resistant leukemia. In this study, human promyelocytic leukemia HL-60cells were selected for the adriamycin (ADM)-resistant phenotype, imitating the process of intra-individual chemotherapy, using long-term, intermittent and continuous stepwise increments of ADM concentration, to set up a stable MDR leukemia subline (HL-60/R). We then dynamically observed the effect on their drug sensitivity, expression of drug-resistance-related genes/proteins and their function, as well as their proteomic and LSC content. We found that after22months ADM-induction, the resistance of HL-60/R to ADM increased85.68-fold over that of their parental HL-60cells, which, meanwhile, cross-tolerated many other chemotherapeutics including cisplatin, daunorubicin, cytarabine, vincristine and etoposide. Additionally, drug-resistance was maintained even after culture in the absence of ADM for3months or6months' refrigeration. Dynamic observations showed that growth speed, cell morphology and cell cycle distribution of HL-60/R cells were distinct from those of HL-60cells, and expression of the transporters ABCC1/MRP1, ABCB1/P-gp, ABCG2/BCRP, and especially mdr1/P-gp, gradually increased with increasing ADM concentration and induction time. Simultaneously, there was a sharp reduction in accumulation of intracellular ADM or rhodamine123(Rh123) and a marked efflux was observed. Protein expression spectrum (proteomics) preliminarily revealed a large number of differentially-expressed proteins in HL-60/R cells compared to parental HL-60cells, which, however, still need further identification by mass spectrometry. The proportion of CD34+CD38-CD123+LSC present, which remarkably enhanced colony-forming ability compared to parental cells, was synchronously increased with the process of ADM-induction in total HL-60cells, and then gradually dropped to almost10%after culture in the absence of ADM with increasing time in culture and as a result of cell multiplication, but increased again upon repeat exposure to ADM, indicating that LSC, due to their characteristics and natural resistance, survived to become the source of leukemia cell proliferation. Simultaneously, because of the repeated stimulus of the cytotoxic drugs, LSC became super-resistant and gained special regulation pathways that were transmitted to the daughter cells which, therefore, became the source of leukemia cells. Interestingly, different from other recognized chemo-resistant leukemia cell lines, the established HL-60/R sub-lines were also strongly cross-resistant to As2O3.
As2O3is widely used in chemotherapy for most types of leukemia and solid tumors. It shows remarkable curative effects and has little cross-resistance with conventional chemotherapeutics. Studies show that most MDR leukemia cells do not manifest cross-resistance but have higher sensitivity to As2O3, and a possible explanation for this may be because As2O3is not a P-gp substrate and may even inhibit P-gp activity. Additionally, cellular arsenic resistance is closely related to arsenic transfer by MPR1, MPR2and ASNA1transporters. In this study, ADM induced MDR in HL-60/R cells. These cells also over-expressed mdrl/P-gp, and were quite resistant to As2O3, to which MDR K562/ADM cells, also induced by ADM and over-expressing P-gp, possess comparatively high sensitivity. To investigate the molecular mechanism underlying the resistance or sensitivity of MDR leukemia cells to As2O3, the drug-resistant K562/ADM cell line, HL-60/R cell line, their parental chemo-sensitive K562cells and HL-60cells were used as model cells to carry out paired-observation expression studies of arsenic transport-related proteins, as well as correlation with arsenic-sensitivity. The results revealed that expression levels of MRP1, MRP2and ASNA1were all lower in K562/ADM cells compared to their parental K562cells and to sensitive HL-60cells, but were highest in HL-60/R cells. As2O3could upregulate MRP1, MRP2and ASNA1in HL-60/R cells but inordinately suppress them in K562/ADM cells. Our study first confirmed whether or not cross-resistance to AS2O3in MDR leukemia cells existed, mainly related to intracellular contents of MPR1, MPR2and ASNA1arsenic transporters and the effect of AS2O3on them.
Our studies showed an outstanding apoptosis-inducing effect and increased expression of GRP78in leukemia K562/ADM cells after arsenic treatment. To explore whether ERS (endoplasmic reticulum stress) is involved in As2O3-mediated apoptosis as well as the inhibitory effect on ABC transporters, we analyzed the effect of changes in expression of ERS-pathway-related genes and proteins including GRP78, CHOP/GADD153, XBP1, caspase-12and Bcl-2. We also investigated the influence of these changes on mdrl/P-gp and Ca2+signaling, comparing results in K562/ADM cells and their parental K562counterparts after As2O3treatment. The results proved that arsenic can induce ERS-related apoptosis in K562/ADM and K562cells by activating the ERS-response signaling pathway. Arsenic can also induce apoptosis in drug-resistant K562/ADM leukemia cells via down-regulation of mdrl/P-gp expression, thus strengthening the UPR(unfolded protein response)-triggered caspase-dependent cell-death pathway and down-regulating Bcl-2expression, consequently promoting Ca2+release and triggering calcium signaling in ERS-induced apoptosis.
In conclusion, leukemia HL-60/R sub-lines acquired chemo-resistance as a result of intermittent and consecutive ADM-resistance-inducing methods and also developed characteristics of over-expression of resistance-related genes/proteins and changes in the protein expression spectrum as well as increases in the LSC population, which, distinct from classical leukemia MDR cells, are also a unique feature of high As2O3-resistance.The source of cellular resistance may be derived from surviving chemo-resistant LSC in the HL-60population subjected to long and consecutive stimulation with ADM. The LSC may adaptively mutate to gain characteristics of high chemo-reagent resistance or develop a special signal-regulated pathway that can be transmitted to their daughter cells to form a new chemo-resistant leukemia cell population. As2O3has been used in chemotherapy for most types of leukemia and solid tumors due to its remarkable curative effects and lack of cross-resistance with conventional chemotherapeutic drugs. However, whether drug-resistant leukemia cells possess cross-resistance to As2O3is closely related to their expression of the arsenic transporters MPR1, MPR2and ASNA1. As2O3induces expression of ERS. down-regulating mdr1/P-gp expression to strengthen the UPR-triggered caspase-dependent cell-death pathway and down-regulating Bcl-2expression. Consequently promoting Ca2+release and triggering calcium signaling in ERS-induced apoptosis are the major cellular and molecular mechanisms underlying the stronger apoptotic effect in some resistant leukemia cells, such as K562/ADM cells.
我们采用阿霉素(Adriamycin, ADM)模拟体内化疗过程,逐步提高药物浓度、长期、间歇性刺激的方法诱导人白血病HL-60细胞获得耐药特性,建立稳定的白血病多药耐药细胞株(HL-60/R),并动态观察白血病细胞获得耐药性的过程中药物敏感性、耐药基因／蛋白表达及功能、蛋白质组、LSC含量等的变化。研究发现,历经22个月的ADM诱导后,耐药性的HL-60/R细胞对ADM的耐受性增高85.68倍,且与顺铂、长春新碱、依托泊苷、阿糖胞苷和柔红霉素等多种化疗药物交叉耐受。HL-60/R细胞在无ADM条件下培养3个月以上或冻存-重新复苏其耐药性均无降低,证明该细胞具备稳定的多药耐药性。动态观察显示,HL-60/R细胞在生长速度、细胞形态以及细胞周期分布等方面均与亲本HL-60细胞有不同程度的差异；随诱导时间延长和诱导药物浓度提高,药物转运蛋白ABCC1/MRP1、 ABCB1/P-gp和ABCG2/BCRP的表达逐步增高,尤以mdrl/P-gp为著,且诱导耐药细胞对ADM或rhodamine123(Rhl23)的蓄积明显减少、外排显著增加。蛋白质表达谱(蛋白质组)初步揭示HL-60/R细胞存在大量的差异表达蛋白,有待进一步的质谱鉴定分析。ADM诱导过程中HL-60细胞群体中表面标志为CD34+CD38-CD123+的的LSC的含量同步增高且HL-60/R细胞较亲本HL-60细胞具有显著增强的集落形成能力。ADM诱导后的HL-60细胞在无ADM培养基中随着扩增培养时间延长,细胞群体中LSC的比例逐渐降低,稳定在10%左右,ADM重新诱导复又增高。提示在ADM的长期反复诱导过程中HL-60细胞群体中的LSC因其天然耐药性而存活下来,并可能因药物的反复诱导而获得高耐药特性和独特调控通路,成为耐药性白血病细胞群体的源泉。有趣的是,不同于其它已知的多药耐药性白血病细胞,我们诱导建立的HL-60/R对三氧化二砷(arsenic trioxide, AS2O3)具有很强的交叉耐受性。
As203因具有显著疗效且与常规抗肿瘤药物无交叉耐药性而被广泛用于白血病及实体肿瘤的治疗,取得显著的疗效。研究证实大多数MDR白血病细胞并不对As203产生交叉耐药性,甚至具有更高的敏感性,可能与As203并非P-gp的底物且能抑制P-gp活性有关,同时,细胞的抗砷性与MPR1、MPR2和ASNA1等转运蛋白对砷的转运密切相关。我们采用ADM诱导的mdr1/P-gp高表达的HL-60/R耐药细胞对As203高度耐受,但同样是ADM诱导和mdr1/P-gp高表达的K562/ADM耐药细胞却对As203具有高敏感性。为探讨白血病MDR细胞对As203耐受还是敏感的分子机制,我们对比观察了对K562/ADM细胞、HL-60/R细胞及其亲本药物敏感的K562细胞和HL-60细胞砷转运相关蛋白的表达,以及与对As203敏感性的相关性。结果揭示，与亲本K562细胞和HL-60细胞相比较,K562/ADM细胞具有较低的MRP1、MRP2和ASNA1的表达,而HL-60/R细胞则表达更高,且明显高于K562/ADM细胞。As203促进HL-60/R细胞MRP1、MRP2和ASNA1的表达,却对K562/ADM细胞的表达具有不同程度的抑制作用。我们的研究首次证实对常规抗肿瘤药物抵抗的白血病耐药细胞是否与As203交叉耐受,主要与耐药细胞MPR1、 MPR2和ASNA1等砷转运相关蛋白的表达水平,以及As203作用对这些转运蛋白表达的影响密切相关。
我们的研究证实As203对白血病K562/ADM耐药细胞具有较高的凋亡诱导效应,且可明显提高内质网分子伴侣GRP78/Bip的表达。为探讨除As203抑制ABC转运蛋白表达外,内质网应激(endoplasmic reticulum stress, ERS)反应是否参与K562/ADM细胞对As203诱导凋亡敏感性的机制,我们进一步比较研究了As203诱导K562/ADM细胞及其亲本K562细胞凋亡过程中GRP78、CHOP/GADD153、 XBP1和caspase-12等内质网应激相关基因/蛋白和rndr1/P-gp、Bcl-2等耐药相关基因/蛋白的表达改变,以及Ca2+信号变化。研究结果证实As203可激活内质网应激反应的信号通路而诱发K562/ADM细胞和K562细胞发生内质网应激反应,并通过下调mdr1/P-gp表达增强未折叠蛋白反应(unfolded protein response, UPR)触发caspase依赖的细胞凋亡途径,下调Bcl-2促进Ca2+释放而启动内质网应激性凋的钙离子起始信号,诱导耐药性白血病K562/ADM细胞发生更强的内质网应激反应性细胞凋亡。
综上所述,采用ADM长期、反复、间歇性地提高药物浓度诱导白血病HL-60细胞(HL-60/R)获得了稳定的多药耐药特性,并具备高表达耐药相关基因/蛋白、蛋白质表达谱改变和LSC含量增高等特性,且与经典白血病MDR细胞不同,HL-60/R细胞具有对As203高耐受性的独特特性。ADM诱导耐药性的源泉可能为长期反复诱导过程中HL-60细胞群体中存活的耐药性LSC, LSC可能会因反复暴露于药物而发生适应性突变获得高耐药特性或独特调控信号通路,并传递给其后代细胞而形成耐药性白血病细胞群体。As203因与常规抗肿瘤药物无交叉耐药性而被用于耐药性白血病的治疗,但耐药性白血病细胞是否与As203交叉耐受,与其MPR1、MPR2和ASNA1等砷转运相关蛋白的表达及As203对转运蛋白表达的影响密切相关。As203激发内质网应激反应,并通过下调1ndr1/P-gp表达增强UPR触发caspase依赖的细胞死亡通路和下调Bcl-2促进Ca2+释放而启动内质网应激性细胞凋亡的钙离子起始信号,是其诱发某些耐药性白血病细胞如K562/ADM细胞更强凋亡效应的主要细胞分子机制。
The phenomenon of acquired multi-drug resistance (MDR) in leukemia is one of the major and pivotal impediments in leukemia therapy which has not yet been overcome. Over many years, a large number of extensive studies around leukemia drug-resistance, regulatory pathways and intervention measures have been launched but so far, the mechanisms remain incompletely understood and few effective or clinically practical countermeasures have been identified.Recently, the cardinal role of leukemia stem cells (LSC) in leukemia-MDR has attracted widespread attention and it has been speculated that they are the core factor underlying leukemia drug resistance and also the key cause of conventional chemotherapy failure and relapse in leukemia. Therefore, it is necessary to study the resistance characteristics of leukemia and its cellular and molecular mechanisms and to specifically explore ways to overcome these to provide new potential targets for clinical treatment of drug-resistant leukemia. In this study, human promyelocytic leukemia HL-60cells were selected for the adriamycin (ADM)-resistant phenotype, imitating the process of intra-individual chemotherapy, using long-term, intermittent and continuous stepwise increments of ADM concentration, to set up a stable MDR leukemia subline (HL-60/R). We then dynamically observed the effect on their drug sensitivity, expression of drug-resistance-related genes/proteins and their function, as well as their proteomic and LSC content. We found that after22months ADM-induction, the resistance of HL-60/R to ADM increased85.68-fold over that of their parental HL-60cells, which, meanwhile, cross-tolerated many other chemotherapeutics including cisplatin, daunorubicin, cytarabine, vincristine and etoposide. Additionally, drug-resistance was maintained even after culture in the absence of ADM for3months or6months' refrigeration. Dynamic observations showed that growth speed, cell morphology and cell cycle distribution of HL-60/R cells were distinct from those of HL-60cells, and expression of the transporters ABCC1/MRP1, ABCB1/P-gp, ABCG2/BCRP, and especially mdr1/P-gp, gradually increased with increasing ADM concentration and induction time. Simultaneously, there was a sharp reduction in accumulation of intracellular ADM or rhodamine123(Rh123) and a marked efflux was observed. Protein expression spectrum (proteomics) preliminarily revealed a large number of differentially-expressed proteins in HL-60/R cells compared to parental HL-60cells, which, however, still need further identification by mass spectrometry. The proportion of CD34+CD38-CD123+LSC present, which remarkably enhanced colony-forming ability compared to parental cells, was synchronously increased with the process of ADM-induction in total HL-60cells, and then gradually dropped to almost10%after culture in the absence of ADM with increasing time in culture and as a result of cell multiplication, but increased again upon repeat exposure to ADM, indicating that LSC, due to their characteristics and natural resistance, survived to become the source of leukemia cell proliferation. Simultaneously, because of the repeated stimulus of the cytotoxic drugs, LSC became super-resistant and gained special regulation pathways that were transmitted to the daughter cells which, therefore, became the source of leukemia cells. Interestingly, different from other recognized chemo-resistant leukemia cell lines, the established HL-60/R sub-lines were also strongly cross-resistant to As2O3.
As2O3is widely used in chemotherapy for most types of leukemia and solid tumors. It shows remarkable curative effects and has little cross-resistance with conventional chemotherapeutics. Studies show that most MDR leukemia cells do not manifest cross-resistance but have higher sensitivity to As2O3, and a possible explanation for this may be because As2O3is not a P-gp substrate and may even inhibit P-gp activity. Additionally, cellular arsenic resistance is closely related to arsenic transfer by MPR1, MPR2and ASNA1transporters. In this study, ADM induced MDR in HL-60/R cells. These cells also over-expressed mdrl/P-gp, and were quite resistant to As2O3, to which MDR K562/ADM cells, also induced by ADM and over-expressing P-gp, possess comparatively high sensitivity. To investigate the molecular mechanism underlying the resistance or sensitivity of MDR leukemia cells to As2O3, the drug-resistant K562/ADM cell line, HL-60/R cell line, their parental chemo-sensitive K562cells and HL-60cells were used as model cells to carry out paired-observation expression studies of arsenic transport-related proteins, as well as correlation with arsenic-sensitivity. The results revealed that expression levels of MRP1, MRP2and ASNA1were all lower in K562/ADM cells compared to their parental K562cells and to sensitive HL-60cells, but were highest in HL-60/R cells. As2O3could upregulate MRP1, MRP2and ASNA1in HL-60/R cells but inordinately suppress them in K562/ADM cells. Our study first confirmed whether or not cross-resistance to AS2O3in MDR leukemia cells existed, mainly related to intracellular contents of MPR1, MPR2and ASNA1arsenic transporters and the effect of AS2O3on them.
Our studies showed an outstanding apoptosis-inducing effect and increased expression of GRP78in leukemia K562/ADM cells after arsenic treatment. To explore whether ERS (endoplasmic reticulum stress) is involved in As2O3-mediated apoptosis as well as the inhibitory effect on ABC transporters, we analyzed the effect of changes in expression of ERS-pathway-related genes and proteins including GRP78, CHOP/GADD153, XBP1, caspase-12and Bcl-2. We also investigated the influence of these changes on mdrl/P-gp and Ca2+signaling, comparing results in K562/ADM cells and their parental K562counterparts after As2O3treatment. The results proved that arsenic can induce ERS-related apoptosis in K562/ADM and K562cells by activating the ERS-response signaling pathway. Arsenic can also induce apoptosis in drug-resistant K562/ADM leukemia cells via down-regulation of mdrl/P-gp expression, thus strengthening the UPR(unfolded protein response)-triggered caspase-dependent cell-death pathway and down-regulating Bcl-2expression, consequently promoting Ca2+release and triggering calcium signaling in ERS-induced apoptosis.
In conclusion, leukemia HL-60/R sub-lines acquired chemo-resistance as a result of intermittent and consecutive ADM-resistance-inducing methods and also developed characteristics of over-expression of resistance-related genes/proteins and changes in the protein expression spectrum as well as increases in the LSC population, which, distinct from classical leukemia MDR cells, are also a unique feature of high As2O3-resistance.The source of cellular resistance may be derived from surviving chemo-resistant LSC in the HL-60population subjected to long and consecutive stimulation with ADM. The LSC may adaptively mutate to gain characteristics of high chemo-reagent resistance or develop a special signal-regulated pathway that can be transmitted to their daughter cells to form a new chemo-resistant leukemia cell population. As2O3has been used in chemotherapy for most types of leukemia and solid tumors due to its remarkable curative effects and lack of cross-resistance with conventional chemotherapeutic drugs. However, whether drug-resistant leukemia cells possess cross-resistance to As2O3is closely related to their expression of the arsenic transporters MPR1, MPR2and ASNA1. As2O3induces expression of ERS. down-regulating mdr1/P-gp expression to strengthen the UPR-triggered caspase-dependent cell-death pathway and down-regulating Bcl-2expression. Consequently promoting Ca2+release and triggering calcium signaling in ERS-induced apoptosis are the major cellular and molecular mechanisms underlying the stronger apoptotic effect in some resistant leukemia cells, such as K562/ADM cells.
引文
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