基因OLA1（Obg Like ATPase 1）的蛋白功能研究
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摘要
研究背景:
在真核细胞中,谷胱甘肽(Glutathione;GSH)是丰度最高的小分子肽。作为一种非常重要的非蛋白巯基分子,参与了一系列的细胞生理活动:其作为一种还原剂和抗氧化剂,参与了大量的细胞外源性和内源性分子的生理代谢;作为一种自由基清除剂,因为活性氧(ROS)和活性氮自由基(RNS)在细胞信号传导和许多病理发展过程中扮演了非常重要的角色,所以谷胱甘肽在含量与生理代谢上的改变被认为和很多疾病有联系,包括肿瘤,神经系统疾病,艾滋病,衰老,囊性纤维化,肝病,心脏病,中风,糖尿病以及营养不良症。
为了进一步理解GSH的抗氧化调节及其对机体各种生理活动的影响,数年以前,我们实验组成员施正政等人用遗传学的方法在小鼠胚胎细胞中把谷氨酰半胱氨酸合成酶的重链基因敲除而得到自身不能合成GSH的小鼠胚胎,并把囊胚细胞分离出来进行体外培养。这些突变型的囊胚细胞在含有GSH或者N-乙酰半胱氨酸(N-acetylcysteine;NAC)的培养基中能够正常生长和无限繁殖,但是当GSH或者NAC没有得到补充时,细胞都会死亡。用基因芯片的技术来研究GSH被剥夺之后突变型细胞内基因表达的变化,结果分析显示有32个基因有显著的差异表达。按照生物学功能分类,这些基因的功能包括细胞周期调控,细胞凋亡调控,生理代谢调控以及未知功能。OLA1(Obg-like ATPase;GTPBP9;PTD004)就是这32个基因中的一个,而且目前生理学功能未知。
研究内容:
而本文将对这个未知功能的基因-OLA1(Obg-like ATPase;GTPBP9;PTD004)进行初步的研究,希望能了解该基因在细胞生理活动中的功能,并进一步理解该基因在GSH参与的细胞生长和抗氧化调节中的作用,从而增进我们对细胞内抗氧化反应和肿瘤发生发展的了解,为治疗和预防肿瘤提供新的思路和方法。研究内容共分三部分:(一)蛋白结构,表达与功能分析;(二)调控抗氧化机制研究;(三)在肿瘤转移和侵袭中的作用。
(一)蛋白结构,表达与功能分析
我们通过生物信息学分析表明OLA1属于Obg一类的GTPase家族,与P-loopNTPase-YchF同源。其蛋白含有396个氨基酸,已知的结构域有位于N端的Gdomain,其两侧有coiled-coil domain,还包括在C端的TGS domain。通过在GeneBank序列库对比发现,OLA1基因和蛋白序列在酵母,小鼠和人类中的同源性极高,表明OLA1是相对保守的基因。我们用Western blotting方法在16中人类肿瘤和正常细胞系中检测发现,OLA1是一个广泛表达的基因,在多种肿瘤和正常细胞系中都有表达。我们通过免疫荧光的方法和在细胞内转染GFP融合表达质粒,在荧光显微镜下观察到OLA1蛋白定位在胞浆。
(二)调控抗氧化机制研究
首先我们用siRNA转染的方法来降低其在细胞内的表达,并用Western blotting方法来检测其knockdown的效果,在转染48小时后,与对照相比,knockdown细胞蛋白水平下降80%以上。而且在用细胞计数,PI染色和Annexin V染色技术,发现knockdown细胞的细胞周期和增殖速率,死亡率和对照组细胞没有差异。但是当加入氧化剂包括diamide-巯基氧化剂和tert-butyl hydroperoxide(tBH)-过氧化剂处理5小时后,用MTS方法来检查细胞活力时,发现对照组细胞由于氧化压力的原因开始出现大量死亡,而knockdown细胞的死亡率却比较低,仍能维持相对正常的生理活动。另一方面,当我们用质粒瞬时转染细胞使OLA1在细胞内过表达后,过表达的细胞对这些氧化剂变得更敏感,更容易因氧化压力而死亡。但是无论是OLA1低表达或过表达都没有改变细胞对有线粒体毒性或DNA毒性的药物的敏感性,包括antimycin A,etoposide,和doxorubincine,这说明OLA1对细胞的抗氧化能力的条件是有特异性的。
当我们用H2DCFDA染色并通过流式细胞技术来观测细胞内的活性氧水平(ROS),发现在加200μM tBH处理1小时,对照细胞中的ROS水平增加幅度显著高于knockdown细胞(71.4%vs.36%),这表明OLA1-knockdown之后能抑制应激产生的大量ROS。当用bioluminescence-based assay来检测细胞内的GSH含量时,发现在400μM tBH或者400μM diamide处理1小时,knockdown细胞内的GSH含量仍能保持在相对较高的水平。同时,我们用基因芯片的方法来研究knockdown之后细胞内基因表达的变化情况,结果显示OLA1-knockdown所带来的基因表达变化很小,在严格的统计学挑选条件下,共有13个基因发现表达有差异,而且目前的研究没有发现这些基因和细胞抗氧化能力改变有直接的因果关系。而且当加入20μg/ml cycloheximide后,细胞内的蛋白合成被阻止,但MTS检测细胞活力显示,相比对照组细胞,knockdown细胞仍表现出对这些氧化剂具有较高的抵抗力。这有力说明OLA1作为细胞抗氧化反应的负调控因子,其作用机制是不依赖新的蛋白合成,而是对现存的蛋白的修饰,调节其功能来实现的。
(三)在肿瘤转移和侵袭中的作用
ROS作为信号传导的中介,参与了肿瘤转移的多个环节包括肿瘤细胞迁移和侵入。而OLA1对细胞内的ROS水平具有非常迅速的调节作用,所以很有可能通过调控ROS而参与了细胞转移这个过程。在“创伤-愈合”实验中发现,knockdown细胞的迁移速率大约只有对照细胞的55%,具有迁移细胞特征的细胞数目比例减少到42%,而对照组细胞占78%,表现出迁移受阻的现象。Cell migration assay和cell invasion assay显示,在人类乳腺癌细胞MBA-MD-231中,OLA1被knockdown后,细胞的迁移和侵入被抑制,分别下降了43%和78%。而且同时knockdown细胞内应激产生的ROS水平被抑制。当我们用还原剂N-acetylcysteine 5 mM处理细胞后发现,在“创伤-愈合”实验中,无论是knockdown细胞还是对照组细胞,“创伤”两侧细胞内的ROS被显著下调,同时两组之间细胞的向“创伤”迁移的活动受阻。Cell invasion assay显示,加入N-acetylcysteine后,knockdown细胞和对照组细胞侵入活动也被明显的抑制,都只有原来的20%左右。这表明OLA1-knockdown后,对肿瘤细胞迁移和侵入能力的抑制很可能是通过调节细胞内的ROS水平来实现的。
结论与创新:
1.本研究首次发现一个新的细胞内抗氧化反应的负调控因子-OLA1,它对细胞内抗氧化机制具有特异的调节性,主要是针对细胞内的还原型巯基的动态平衡。
2.本研究发现了新的抗氧化调节机制,证明OLA1对细胞抗氧化机制的调节是通过蛋白翻译后调节来实现的,而不像大部分的调节途径需要从基因转录开始,因而反应更迅速。
3.本研究首次发现因为OLA1被knockdown之后,导致肿瘤细胞的迁移和侵入能力被抑制,转移能力下降,并且这很可能是通过调节ROS来实现的。
而且OLA1作为一个ATPase,具有很好的作为药物靶点的结构,因此发现抑制OLA1表达和功能的小分子药物在针对抗氧化和抑制肿瘤转移的临床应用中会有很广阔的前景。
Glutathione (L-γ-glutamyl-L-cysteinyl-glycine; GSH), the most prevalent non-protein thiol in mammalian cells and the most abundant low molecular weight peptide present in eukaryotic cells. Today the implication of GSH in many cellular functions has been recognized. GSH acts as a reducing agent and an antioxidant, is involved in the metabolism of xenobiotics and different cell molecules, is a free-radical scavenger, and has a role in cell-cycle regulation and microtubular-related mechanisms. Due to these functions and to the roles of reactive oxygen (ROS) and nitrogen (RNS) species in cell signaling and in many human pathological processes, alterations in GSH levels and metabolism have been associated with different human diseases, including cancer, neurodegenerative diseases, acquired immune deficiency syndrome (AIDS), aging, cystic fibrosis, liver diseases, heart attack, stroke, seizure, diabetes, sickle cell anemia, and kwashiorkor.
In order to further study the effects of lack of glutathione on cellular physiological activities, we developed mice deficient in the heavy subunit ofγ-glutamyl cysteine synthetase. We have successfully isolated cell lines from homozygous mutant blastocysts by culturing them in medium containing GSH. SuchγGCS-deficient cells grew for only a few days in the absence of GSH or NAC: cellular GSH drops to an undetectable level within 24 hours and cells eventually die. The microarray was applied to study the gene expression changes during this process. We have identified 32 candidate clones the expression of which either increases or decreases at least twofold 24 hours after the withdrawal of GSH. Database analysis suggested that these genes fell within the functional categories of cell cycle, apoptosis, metabolism, and unknown function. In the present study, we have performed functional characterizations on one of the gene products, originally named GTPBP9 or PTD004, and recently defined as a new member of the Obg-like ATPase family-OLA1, in human cells.
OLA1, as the homolog of the E. coli P-loop NTPase YchF, is a member of the Obg-related family of GTPases belonging to the TRAFAC (translation factors) class. The deduced 396-amino acid protein consists of an N-terminal G domain, flanked on either side by an inserted coiled-coil, and a C-terminal TGS domain. It is a conserved gene and ubiquitinly expressed in many cell lines.
When OLA1 was knocked down with short interference RNA (siRNA), cells gained more resistance to the cytotoxicity of diamide, a glutathione oxidation agent, and tert-butyl hydroperoxide (tBH), a peroxide oxidant. On the other hand, when OLA1 is overexpressed by plasmid transfection, cells became more sensitive to these stressors. However, knockdown of OLA1 exhibited no changes in the sensitivity of cells to mitochondria- or DNA-damaging agents including antimycin A, etoposide, and doxorubincine. Moreover, no notable difference in cell proliferation and baseline apoptosis was seen in the OLA1-knockdown cells.
We further investigated the levels of reactive oxygen species (ROS) in the Ola1-knockdown cells by flow cytometry after DCFDA staining, and confirmed a significant decrease in ROS production of intracellular ROS when the cells were briefly challenged with tBH, as compared with the cells transfected with non-targeting siRNA. Meanwhile we have shown that the OLA1-knockdown cells maintained a higher level of reduced glutathione from the very beginning of the treatment of either diamide or tBH. In order to understand why the cells possess more reduced glutathione and/or can better sustain the oxidation of glutathione, we performed a genome-wide expression assay using the Agilent microarrays. Surprisingly, the knockdown of OLA1 caused only a minimal genomic response, and neither genes encoding antioxidant enzymes and enzymes for producing antioxidants (such as glutathione) were found to have any detectable changes at the mRNA level. Moreover, when de novo protein synthesis was blocked by cycloheximide in OLA1-knockdown cells, they continued to demonstrate increased resistance to both tBH and diamide. These data demonstrate that OLA1 suppresses the antioxidant response through nontranscriptional mechanisms.
Moreover, we found that OLA1 played a very important role in cancer metastasis. Reactive oxygen species (ROS) are proposed to be signaling intermediates involved in metastatic processes including cell migration and invasion. We found that siRNA-mediated knockdown of OLA1 significantly inhibited cell migration and invasion in breast cancer cell line MBA-MD-231, as assessed by in vitro cell migration and invasion assays, respectively. Knockdown of OLA1 caused no changes in cell growth but affected ROS production. In wound-healing assays, decreased ROS in OLA1-knockdown cells were in situ associated with the cells' decreased motile morphology. Further, treatment of N-acetylcysteine, a general ROS scavenger, blunted the motility and invasiveness of MDA-MB-231, similar to the effect of OLA1-knockdown. These results suggest that knockdown of OLA1 inhibits breast cancer cell migration and invasion through a mechanism that involves the modulation of intracellular ROS levels.
Taken together, our data suggest that OLA1 is a novel negative regulator specifically for the cellular anti-oxidative response system, and that this regulation is through a post-translational mechanism (e.g., enzymatic activity modulation and protein degradation). And knockdown of OLA1 could impair the cell migration and invasion ability, meaning a potential clinical application. Further, since the OLA1 protein is an ATPase, a common druggable structure, the above beneficial effects associated with the OLA1-knockdown may implicate OLA1 as a drug target for anti-oxidative and anti-metastasis therapy.
在真核细胞中,谷胱甘肽(Glutathione;GSH)是丰度最高的小分子肽。作为一种非常重要的非蛋白巯基分子,参与了一系列的细胞生理活动:其作为一种还原剂和抗氧化剂,参与了大量的细胞外源性和内源性分子的生理代谢;作为一种自由基清除剂,因为活性氧(ROS)和活性氮自由基(RNS)在细胞信号传导和许多病理发展过程中扮演了非常重要的角色,所以谷胱甘肽在含量与生理代谢上的改变被认为和很多疾病有联系,包括肿瘤,神经系统疾病,艾滋病,衰老,囊性纤维化,肝病,心脏病,中风,糖尿病以及营养不良症。
为了进一步理解GSH的抗氧化调节及其对机体各种生理活动的影响,数年以前,我们实验组成员施正政等人用遗传学的方法在小鼠胚胎细胞中把谷氨酰半胱氨酸合成酶的重链基因敲除而得到自身不能合成GSH的小鼠胚胎,并把囊胚细胞分离出来进行体外培养。这些突变型的囊胚细胞在含有GSH或者N-乙酰半胱氨酸(N-acetylcysteine;NAC)的培养基中能够正常生长和无限繁殖,但是当GSH或者NAC没有得到补充时,细胞都会死亡。用基因芯片的技术来研究GSH被剥夺之后突变型细胞内基因表达的变化,结果分析显示有32个基因有显著的差异表达。按照生物学功能分类,这些基因的功能包括细胞周期调控,细胞凋亡调控,生理代谢调控以及未知功能。OLA1(Obg-like ATPase;GTPBP9;PTD004)就是这32个基因中的一个,而且目前生理学功能未知。
研究内容:
而本文将对这个未知功能的基因-OLA1(Obg-like ATPase;GTPBP9;PTD004)进行初步的研究,希望能了解该基因在细胞生理活动中的功能,并进一步理解该基因在GSH参与的细胞生长和抗氧化调节中的作用,从而增进我们对细胞内抗氧化反应和肿瘤发生发展的了解,为治疗和预防肿瘤提供新的思路和方法。研究内容共分三部分:(一)蛋白结构,表达与功能分析;(二)调控抗氧化机制研究;(三)在肿瘤转移和侵袭中的作用。
(一)蛋白结构,表达与功能分析
我们通过生物信息学分析表明OLA1属于Obg一类的GTPase家族,与P-loopNTPase-YchF同源。其蛋白含有396个氨基酸,已知的结构域有位于N端的Gdomain,其两侧有coiled-coil domain,还包括在C端的TGS domain。通过在GeneBank序列库对比发现,OLA1基因和蛋白序列在酵母,小鼠和人类中的同源性极高,表明OLA1是相对保守的基因。我们用Western blotting方法在16中人类肿瘤和正常细胞系中检测发现,OLA1是一个广泛表达的基因,在多种肿瘤和正常细胞系中都有表达。我们通过免疫荧光的方法和在细胞内转染GFP融合表达质粒,在荧光显微镜下观察到OLA1蛋白定位在胞浆。
(二)调控抗氧化机制研究
首先我们用siRNA转染的方法来降低其在细胞内的表达,并用Western blotting方法来检测其knockdown的效果,在转染48小时后,与对照相比,knockdown细胞蛋白水平下降80%以上。而且在用细胞计数,PI染色和Annexin V染色技术,发现knockdown细胞的细胞周期和增殖速率,死亡率和对照组细胞没有差异。但是当加入氧化剂包括diamide-巯基氧化剂和tert-butyl hydroperoxide(tBH)-过氧化剂处理5小时后,用MTS方法来检查细胞活力时,发现对照组细胞由于氧化压力的原因开始出现大量死亡,而knockdown细胞的死亡率却比较低,仍能维持相对正常的生理活动。另一方面,当我们用质粒瞬时转染细胞使OLA1在细胞内过表达后,过表达的细胞对这些氧化剂变得更敏感,更容易因氧化压力而死亡。但是无论是OLA1低表达或过表达都没有改变细胞对有线粒体毒性或DNA毒性的药物的敏感性,包括antimycin A,etoposide,和doxorubincine,这说明OLA1对细胞的抗氧化能力的条件是有特异性的。
当我们用H2DCFDA染色并通过流式细胞技术来观测细胞内的活性氧水平(ROS),发现在加200μM tBH处理1小时,对照细胞中的ROS水平增加幅度显著高于knockdown细胞(71.4%vs.36%),这表明OLA1-knockdown之后能抑制应激产生的大量ROS。当用bioluminescence-based assay来检测细胞内的GSH含量时,发现在400μM tBH或者400μM diamide处理1小时,knockdown细胞内的GSH含量仍能保持在相对较高的水平。同时,我们用基因芯片的方法来研究knockdown之后细胞内基因表达的变化情况,结果显示OLA1-knockdown所带来的基因表达变化很小,在严格的统计学挑选条件下,共有13个基因发现表达有差异,而且目前的研究没有发现这些基因和细胞抗氧化能力改变有直接的因果关系。而且当加入20μg/ml cycloheximide后,细胞内的蛋白合成被阻止,但MTS检测细胞活力显示,相比对照组细胞,knockdown细胞仍表现出对这些氧化剂具有较高的抵抗力。这有力说明OLA1作为细胞抗氧化反应的负调控因子,其作用机制是不依赖新的蛋白合成,而是对现存的蛋白的修饰,调节其功能来实现的。
(三)在肿瘤转移和侵袭中的作用
ROS作为信号传导的中介,参与了肿瘤转移的多个环节包括肿瘤细胞迁移和侵入。而OLA1对细胞内的ROS水平具有非常迅速的调节作用,所以很有可能通过调控ROS而参与了细胞转移这个过程。在“创伤-愈合”实验中发现,knockdown细胞的迁移速率大约只有对照细胞的55%,具有迁移细胞特征的细胞数目比例减少到42%,而对照组细胞占78%,表现出迁移受阻的现象。Cell migration assay和cell invasion assay显示,在人类乳腺癌细胞MBA-MD-231中,OLA1被knockdown后,细胞的迁移和侵入被抑制,分别下降了43%和78%。而且同时knockdown细胞内应激产生的ROS水平被抑制。当我们用还原剂N-acetylcysteine 5 mM处理细胞后发现,在“创伤-愈合”实验中,无论是knockdown细胞还是对照组细胞,“创伤”两侧细胞内的ROS被显著下调,同时两组之间细胞的向“创伤”迁移的活动受阻。Cell invasion assay显示,加入N-acetylcysteine后,knockdown细胞和对照组细胞侵入活动也被明显的抑制,都只有原来的20%左右。这表明OLA1-knockdown后,对肿瘤细胞迁移和侵入能力的抑制很可能是通过调节细胞内的ROS水平来实现的。
结论与创新:
1.本研究首次发现一个新的细胞内抗氧化反应的负调控因子-OLA1,它对细胞内抗氧化机制具有特异的调节性,主要是针对细胞内的还原型巯基的动态平衡。
2.本研究发现了新的抗氧化调节机制,证明OLA1对细胞抗氧化机制的调节是通过蛋白翻译后调节来实现的,而不像大部分的调节途径需要从基因转录开始,因而反应更迅速。
3.本研究首次发现因为OLA1被knockdown之后,导致肿瘤细胞的迁移和侵入能力被抑制,转移能力下降,并且这很可能是通过调节ROS来实现的。
而且OLA1作为一个ATPase,具有很好的作为药物靶点的结构,因此发现抑制OLA1表达和功能的小分子药物在针对抗氧化和抑制肿瘤转移的临床应用中会有很广阔的前景。
Glutathione (L-γ-glutamyl-L-cysteinyl-glycine; GSH), the most prevalent non-protein thiol in mammalian cells and the most abundant low molecular weight peptide present in eukaryotic cells. Today the implication of GSH in many cellular functions has been recognized. GSH acts as a reducing agent and an antioxidant, is involved in the metabolism of xenobiotics and different cell molecules, is a free-radical scavenger, and has a role in cell-cycle regulation and microtubular-related mechanisms. Due to these functions and to the roles of reactive oxygen (ROS) and nitrogen (RNS) species in cell signaling and in many human pathological processes, alterations in GSH levels and metabolism have been associated with different human diseases, including cancer, neurodegenerative diseases, acquired immune deficiency syndrome (AIDS), aging, cystic fibrosis, liver diseases, heart attack, stroke, seizure, diabetes, sickle cell anemia, and kwashiorkor.
In order to further study the effects of lack of glutathione on cellular physiological activities, we developed mice deficient in the heavy subunit ofγ-glutamyl cysteine synthetase. We have successfully isolated cell lines from homozygous mutant blastocysts by culturing them in medium containing GSH. SuchγGCS-deficient cells grew for only a few days in the absence of GSH or NAC: cellular GSH drops to an undetectable level within 24 hours and cells eventually die. The microarray was applied to study the gene expression changes during this process. We have identified 32 candidate clones the expression of which either increases or decreases at least twofold 24 hours after the withdrawal of GSH. Database analysis suggested that these genes fell within the functional categories of cell cycle, apoptosis, metabolism, and unknown function. In the present study, we have performed functional characterizations on one of the gene products, originally named GTPBP9 or PTD004, and recently defined as a new member of the Obg-like ATPase family-OLA1, in human cells.
OLA1, as the homolog of the E. coli P-loop NTPase YchF, is a member of the Obg-related family of GTPases belonging to the TRAFAC (translation factors) class. The deduced 396-amino acid protein consists of an N-terminal G domain, flanked on either side by an inserted coiled-coil, and a C-terminal TGS domain. It is a conserved gene and ubiquitinly expressed in many cell lines.
When OLA1 was knocked down with short interference RNA (siRNA), cells gained more resistance to the cytotoxicity of diamide, a glutathione oxidation agent, and tert-butyl hydroperoxide (tBH), a peroxide oxidant. On the other hand, when OLA1 is overexpressed by plasmid transfection, cells became more sensitive to these stressors. However, knockdown of OLA1 exhibited no changes in the sensitivity of cells to mitochondria- or DNA-damaging agents including antimycin A, etoposide, and doxorubincine. Moreover, no notable difference in cell proliferation and baseline apoptosis was seen in the OLA1-knockdown cells.
We further investigated the levels of reactive oxygen species (ROS) in the Ola1-knockdown cells by flow cytometry after DCFDA staining, and confirmed a significant decrease in ROS production of intracellular ROS when the cells were briefly challenged with tBH, as compared with the cells transfected with non-targeting siRNA. Meanwhile we have shown that the OLA1-knockdown cells maintained a higher level of reduced glutathione from the very beginning of the treatment of either diamide or tBH. In order to understand why the cells possess more reduced glutathione and/or can better sustain the oxidation of glutathione, we performed a genome-wide expression assay using the Agilent microarrays. Surprisingly, the knockdown of OLA1 caused only a minimal genomic response, and neither genes encoding antioxidant enzymes and enzymes for producing antioxidants (such as glutathione) were found to have any detectable changes at the mRNA level. Moreover, when de novo protein synthesis was blocked by cycloheximide in OLA1-knockdown cells, they continued to demonstrate increased resistance to both tBH and diamide. These data demonstrate that OLA1 suppresses the antioxidant response through nontranscriptional mechanisms.
Moreover, we found that OLA1 played a very important role in cancer metastasis. Reactive oxygen species (ROS) are proposed to be signaling intermediates involved in metastatic processes including cell migration and invasion. We found that siRNA-mediated knockdown of OLA1 significantly inhibited cell migration and invasion in breast cancer cell line MBA-MD-231, as assessed by in vitro cell migration and invasion assays, respectively. Knockdown of OLA1 caused no changes in cell growth but affected ROS production. In wound-healing assays, decreased ROS in OLA1-knockdown cells were in situ associated with the cells' decreased motile morphology. Further, treatment of N-acetylcysteine, a general ROS scavenger, blunted the motility and invasiveness of MDA-MB-231, similar to the effect of OLA1-knockdown. These results suggest that knockdown of OLA1 inhibits breast cancer cell migration and invasion through a mechanism that involves the modulation of intracellular ROS levels.
Taken together, our data suggest that OLA1 is a novel negative regulator specifically for the cellular anti-oxidative response system, and that this regulation is through a post-translational mechanism (e.g., enzymatic activity modulation and protein degradation). And knockdown of OLA1 could impair the cell migration and invasion ability, meaning a potential clinical application. Further, since the OLA1 protein is an ATPase, a common druggable structure, the above beneficial effects associated with the OLA1-knockdown may implicate OLA1 as a drug target for anti-oxidative and anti-metastasis therapy.
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