钾通道阻断剂对人乳腺上皮细胞增殖的影响及与Caveolin-1蛋白表达关系的研究
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摘要
乳腺癌是女性最常见的恶性肿瘤之一,是乳腺导管上皮细胞在各种内外致癌因素的作用下,失去正常特性而异常增生,以致超过自我修复的限度而发生癌变的疾病。研究表明,许多遗传中与乳腺有关的异常基因和后天受致癌因素影响发生的基因变化参与这一过程。但到目前为止,乳腺上皮细胞恶性转化的分子机制仍不十分清楚,导致乳腺癌发病机理的研究难以取得突破性进展。
Caveolin-1(Cav-1,窖蛋白,曾译为小窝蛋白)是Caveolae(胞膜窖)的标志蛋白,主要表达于终末分化的细胞。近年研究发现, Cav-1与乳腺上皮细胞转化和乳腺癌发生密切相关。在我们实验室前期的研究中,利用基因捕获技术得到稳定传代的Cav-1单倍不足(haploinsufficiency)人乳腺上皮细胞株(MCF10A-ST1),Cav-1的mRNA和蛋白质表达均明显降低。进一步研究证实,Cav-1单倍不足可以通过上调乳腺上皮细胞内增殖相关的MAPK信号转导通路等导致人乳腺上皮细胞早期转化,但与Caveolae内其它信号分子的关系尚不完全清楚。
钾离子通道(K+通道)是细胞膜上具有转运离子能力的一类重要功能蛋白质,参与细胞许多重要的新陈代谢活动,例如,细胞的增殖、溶质转运、体积控制、酶的激活、细胞分泌、基因表达、兴奋性收缩的传递及细胞内通讯等等。近年来发现,乳腺细胞膜上分布着不同类型的K+通道,其生理机能的改变与乳腺癌的发生发展有着重要的联系。已经证实,多种重要的离子通道定位在Caveolae上,其通道活性受Caveolae的调节。
本实验以Cav-1表达水平不同的人乳腺上皮细胞MCF10A、MCF10A-ST1和乳腺癌细胞MCF7为研究对象,首先通过MTT法检测了K+通道阻断剂TEA和4-AP等对三种乳腺细胞和乳腺癌细胞增殖的影响;其次,利用RT-PCR和免疫印迹方法检测了不同Kv通道在三种细胞中的表达水平及免疫共沉淀技术检测了Kv1.5与Cav-1的共表达关系;第三,观察了K+通道阻断剂4-AP作用后对三种细胞中MAPK通路蛋白的影响,旨在探讨K+通道在乳腺细胞早期转化中的作用与Cav-1介导的信号通路的关系,进一步阐明乳腺癌发生、发展的分子机制,为乳腺癌的早期诊断和治疗提供新思路。
得到如下结果:
1. K+通道的特异性阻断剂TEA和Kv通道阻断剂4-AP均对人乳腺上皮细胞MCF10A、MCF10A-ST1和乳腺癌细胞MCF7的增殖具有抑制作用,且呈剂量时间依赖性。提示乳腺细胞上有大量的K+通道或Kv通道存在,而且K+通道对细胞生长十分重要。
2. Kv通道在不同人乳腺上皮细胞中的表达不同,MCF10A细胞中Kv1.5表达水平最高,MCF10A-ST1中表达次之,MCF7细胞中表达最低,而Kv1.2等的表达没有明显差距,这一结果与三种细胞中Cav-1的表达水平一致,且免疫共沉淀显示了Kv1.5与Caveolae具有直接的关系。提示K+通道在乳腺细胞增殖中的作用可能与Cav-1有关。
3. Kv通道阻断剂4-AP可能影响MAPK蛋白磷酸化MAPK蛋白。MCF10A、MCF10A-ST1、MCF7细胞单纯4-AP作用对三种细胞p-ERK1/2表达无影响。进一步,4-AP作用后血清刺激,p-ERK1/2表达水平明显增加。
结论:
1.人乳腺上皮细胞分布不同的Kv通道,影响乳腺细胞的增殖和转化。
2.Kv1.5可能参与乳腺细胞的早期转化过程,其表达和功能可能受Cav-1导的信号通路的调节。
Breast cancer is the most common kind of malignant tumor and a kind of multi-factor influenced cancer. Both of these factors combine to cause gene mutation or the over-expression of oncogene. Varieties of natural genetic and environmental oncogene are involved in the process. However, the molecular mechanism of malignant transformation for breast epithelial cells is still unclear.
Caveolin-1(Cav-1) is the main structural component of non-clathrin, flask-shaped invaginations named Caveolae. Cav-1 is very important in a variety of cellular functions, such as; the endocytic process, homeostasis (both cholesterol and lipid), signal transduction and tumor suppression. Caveolae are thought to serve as sites for the gathering of signaling complexes, thereby facilitating the initiation and cross-talk of signaling events. In previous research, Cav-1 haploinsufficiency cell lines were obtained by using a gene trapping approach , mRNA and protein levels were reduced; furthermore, Cav-1 haploinsufficiencies induce early transformation of human breast epithelial cells by upregulated MAPK signaling pathways. However, the relationship with other signals in Caveolae is still unclear.
Potassium channels (K+ channels) are major signaling molecules expressed in a wide range of tissues where they have significant involvement in determining a variety of cellular functions, including; proliferation, solute transport, volume control, enzyme activity, secretion, invasion, gene expression, excitation-contraction coupling and intercellular communication. Previous reports show that K+ channels are linked to the physical activity of breast cancer cells. A current study has confirmed that a variety of important K+ channels localize on the caveolae and are modulated by caveolae.
In this study, we used MCF0A, MCF10A-ST1 and MCF7 cells which have expressed different levels of Cav-1. First, an MTT assay was used to observe the inhibitory rate of MCF10A, MCF10A-ST1 and MCF7 cells treated with 4-AP and TEA. Second, RT-PCR and western blot techniques were used to analyze the expression of K+ channels. Co-immunoprecipitation was then used to investigate the link between K+ and Caveolin-1. Third, the western blot was again used to detect MAPK signal pathways of MCF10A, MCF10A-ST1, MCF7 cells after being treated with 4-AP. The object of this study was to investigate the effect of K+ channels during the transformation of breast cells and the mechanism of signaling pathways associated with Cav-1; while the aim was to investigate the mechanism of breast cancer’s occurrence and development. Furthermore, another aim was to provide a new method for diagnosis and therapy in breast cancer.
Results:
1. The effects of TEA (K+ channel blocker) and 4-AP (Kv channel blocker) on proliferation of the human breast epithelial cells MCF10A, MCF-10A-ST1 and breast cancer cells MCF7 are dose-time-dependent. Results indicated that many K+ channels and Kv channels distribute on breast cell membranes and they are important in cell growth.
2. The expression of Kv channels of breast cells are different. Expression of Kv1.5, Kv1.2 in MCF10A, MCF10A-ST1, MCF7 indicates that expression of Kv 1.5 (but not Kv1.2) is reduced with breast cancer progression. Expression of Cav-1 is reduced with breast cancer progression and immuno-precipitation studies show that the Kv1.5 is associated with caveolin-1. It suggested that effect of K+ channels in the proliferation of breast cells relate to the role of Cav -1.
3. p-ERK1/2 protein level was not effected by incubation with 4-AP (no serum) after serum starvation. However, p-ERK1 /2 protein levels were increased significantly after incubation with 4-AP (added serum after 4-AP 10min). It indicated that 4-AP might effect the phosphorylation of MAPK in human breast epithelial cells.
Conclusion:
1. The present results demonstrated that a variety of Kv distribute on the breast cell membrane and Kv channels play important role during the transformation and proliferation of human breast epithelial cells.
2. We hypothesize that Kv1.5 might be involved in the early transformation of breast epithelial cells. Its activity and expression were modulated by the signal pathway associated Cav-1.
Caveolin-1(Cav-1,窖蛋白,曾译为小窝蛋白)是Caveolae(胞膜窖)的标志蛋白,主要表达于终末分化的细胞。近年研究发现, Cav-1与乳腺上皮细胞转化和乳腺癌发生密切相关。在我们实验室前期的研究中,利用基因捕获技术得到稳定传代的Cav-1单倍不足(haploinsufficiency)人乳腺上皮细胞株(MCF10A-ST1),Cav-1的mRNA和蛋白质表达均明显降低。进一步研究证实,Cav-1单倍不足可以通过上调乳腺上皮细胞内增殖相关的MAPK信号转导通路等导致人乳腺上皮细胞早期转化,但与Caveolae内其它信号分子的关系尚不完全清楚。
钾离子通道(K+通道)是细胞膜上具有转运离子能力的一类重要功能蛋白质,参与细胞许多重要的新陈代谢活动,例如,细胞的增殖、溶质转运、体积控制、酶的激活、细胞分泌、基因表达、兴奋性收缩的传递及细胞内通讯等等。近年来发现,乳腺细胞膜上分布着不同类型的K+通道,其生理机能的改变与乳腺癌的发生发展有着重要的联系。已经证实,多种重要的离子通道定位在Caveolae上,其通道活性受Caveolae的调节。
本实验以Cav-1表达水平不同的人乳腺上皮细胞MCF10A、MCF10A-ST1和乳腺癌细胞MCF7为研究对象,首先通过MTT法检测了K+通道阻断剂TEA和4-AP等对三种乳腺细胞和乳腺癌细胞增殖的影响;其次,利用RT-PCR和免疫印迹方法检测了不同Kv通道在三种细胞中的表达水平及免疫共沉淀技术检测了Kv1.5与Cav-1的共表达关系;第三,观察了K+通道阻断剂4-AP作用后对三种细胞中MAPK通路蛋白的影响,旨在探讨K+通道在乳腺细胞早期转化中的作用与Cav-1介导的信号通路的关系,进一步阐明乳腺癌发生、发展的分子机制,为乳腺癌的早期诊断和治疗提供新思路。
得到如下结果:
1. K+通道的特异性阻断剂TEA和Kv通道阻断剂4-AP均对人乳腺上皮细胞MCF10A、MCF10A-ST1和乳腺癌细胞MCF7的增殖具有抑制作用,且呈剂量时间依赖性。提示乳腺细胞上有大量的K+通道或Kv通道存在,而且K+通道对细胞生长十分重要。
2. Kv通道在不同人乳腺上皮细胞中的表达不同,MCF10A细胞中Kv1.5表达水平最高,MCF10A-ST1中表达次之,MCF7细胞中表达最低,而Kv1.2等的表达没有明显差距,这一结果与三种细胞中Cav-1的表达水平一致,且免疫共沉淀显示了Kv1.5与Caveolae具有直接的关系。提示K+通道在乳腺细胞增殖中的作用可能与Cav-1有关。
3. Kv通道阻断剂4-AP可能影响MAPK蛋白磷酸化MAPK蛋白。MCF10A、MCF10A-ST1、MCF7细胞单纯4-AP作用对三种细胞p-ERK1/2表达无影响。进一步,4-AP作用后血清刺激,p-ERK1/2表达水平明显增加。
结论:
1.人乳腺上皮细胞分布不同的Kv通道,影响乳腺细胞的增殖和转化。
2.Kv1.5可能参与乳腺细胞的早期转化过程,其表达和功能可能受Cav-1导的信号通路的调节。
Breast cancer is the most common kind of malignant tumor and a kind of multi-factor influenced cancer. Both of these factors combine to cause gene mutation or the over-expression of oncogene. Varieties of natural genetic and environmental oncogene are involved in the process. However, the molecular mechanism of malignant transformation for breast epithelial cells is still unclear.
Caveolin-1(Cav-1) is the main structural component of non-clathrin, flask-shaped invaginations named Caveolae. Cav-1 is very important in a variety of cellular functions, such as; the endocytic process, homeostasis (both cholesterol and lipid), signal transduction and tumor suppression. Caveolae are thought to serve as sites for the gathering of signaling complexes, thereby facilitating the initiation and cross-talk of signaling events. In previous research, Cav-1 haploinsufficiency cell lines were obtained by using a gene trapping approach , mRNA and protein levels were reduced; furthermore, Cav-1 haploinsufficiencies induce early transformation of human breast epithelial cells by upregulated MAPK signaling pathways. However, the relationship with other signals in Caveolae is still unclear.
Potassium channels (K+ channels) are major signaling molecules expressed in a wide range of tissues where they have significant involvement in determining a variety of cellular functions, including; proliferation, solute transport, volume control, enzyme activity, secretion, invasion, gene expression, excitation-contraction coupling and intercellular communication. Previous reports show that K+ channels are linked to the physical activity of breast cancer cells. A current study has confirmed that a variety of important K+ channels localize on the caveolae and are modulated by caveolae.
In this study, we used MCF0A, MCF10A-ST1 and MCF7 cells which have expressed different levels of Cav-1. First, an MTT assay was used to observe the inhibitory rate of MCF10A, MCF10A-ST1 and MCF7 cells treated with 4-AP and TEA. Second, RT-PCR and western blot techniques were used to analyze the expression of K+ channels. Co-immunoprecipitation was then used to investigate the link between K+ and Caveolin-1. Third, the western blot was again used to detect MAPK signal pathways of MCF10A, MCF10A-ST1, MCF7 cells after being treated with 4-AP. The object of this study was to investigate the effect of K+ channels during the transformation of breast cells and the mechanism of signaling pathways associated with Cav-1; while the aim was to investigate the mechanism of breast cancer’s occurrence and development. Furthermore, another aim was to provide a new method for diagnosis and therapy in breast cancer.
Results:
1. The effects of TEA (K+ channel blocker) and 4-AP (Kv channel blocker) on proliferation of the human breast epithelial cells MCF10A, MCF-10A-ST1 and breast cancer cells MCF7 are dose-time-dependent. Results indicated that many K+ channels and Kv channels distribute on breast cell membranes and they are important in cell growth.
2. The expression of Kv channels of breast cells are different. Expression of Kv1.5, Kv1.2 in MCF10A, MCF10A-ST1, MCF7 indicates that expression of Kv 1.5 (but not Kv1.2) is reduced with breast cancer progression. Expression of Cav-1 is reduced with breast cancer progression and immuno-precipitation studies show that the Kv1.5 is associated with caveolin-1. It suggested that effect of K+ channels in the proliferation of breast cells relate to the role of Cav -1.
3. p-ERK1/2 protein level was not effected by incubation with 4-AP (no serum) after serum starvation. However, p-ERK1 /2 protein levels were increased significantly after incubation with 4-AP (added serum after 4-AP 10min). It indicated that 4-AP might effect the phosphorylation of MAPK in human breast epithelial cells.
Conclusion:
1. The present results demonstrated that a variety of Kv distribute on the breast cell membrane and Kv channels play important role during the transformation and proliferation of human breast epithelial cells.
2. We hypothesize that Kv1.5 might be involved in the early transformation of breast epithelial cells. Its activity and expression were modulated by the signal pathway associated Cav-1.
引文
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[9] LA Pardo, D del Camino, A Sanchez, et al. Oncogenic potential of EAG K+ channels. EMBO J, 1999, 18(20): 5540-5547.
[10] Hayashi K, Matsuda S, Machida K. Invasion Activating Caveolin-1 Mutation in Human Scirrhous Breast Cancers. Cancer Res, 2001, 61: 2361-2364.
[11] Zou W, Mcdaneld L.and Smith LM. Caveolin-1 Haploinsufficiency leads to partial transformation of human breast epithelialcells. Anticancer Res, 2003, 23 (6C): 4581 -4586.
[12]张洪,邹伟. Caveolin-1与乳腺癌关系的研究进展.生物化学与分子生物学报, 2007,23(1):23-26.
[13] Ouadid- Ahidouch H, Chaussade F, Roudbaraki M, et al. Kv1. 1 K+ channels identification in human breast carcinoma cells: involvement in cell proliferation. Biochem Biophys Res Commun, 2000, 278:272–277.
[14] Abdul M, Santo A, Hoosein N. Activity of potassium channel-blockers in breast cancer. Anticancer Res, 2003, 23(4): 3347-3351.
[15] L Guo, ZS Li, HL Wang, et al. Carboxyamido-triazole inhibits proliferation of human breast cancer cells via G(2)/M cell cycle arrest and apoptosis. Eur J Pharmacol, 2006, 538(1-3):15-22.
[16] S Roger, P Besson, JY Le Guennec. Involvement of a novel fast inward sodium current in the invasion capacity of a breast cancer cell line. Biochim Biophys Acta, 2003, 1616(2): 107-111.
[17]张勇,杨安钢.周士胜,氯离子通道家族研究进展.医学分子生物学杂志. 2004, 1 (4) :245-248.
[18]田晶,周士胜,陶凌,胡玉珍. NPPB对肝癌细胞增殖的影响.第四军医大学吉林军医学院学报. 2003, 25(2):63-65
[19]马建军,周士胜,保庭毅,等.氯通道阻断剂NPPB对肾癌细胞系GRC-1生长的抑制作用.第四军医大学学报, 2003, 09: 822～824
[20]瓮占平.钾离子通道与肿瘤关系研究进展.国际病理科学与临床杂志, 2005,25(6):488-491.
[21] Scott P. Fraser, James K.J.Diss, Athina-Myrto Chioni. Voltage-Gated Sodium Channel Expression and Potentiation of Human Breast Cancer Metastasis. Clin Cancer Res . 2005, 11(15): 5381– 5389.
[1] Wang Z. Roles of K+ channels in regulating tumour cell proliferation and apoptosis. Pflugers Arch, 2004, 448 (3): 274-286.
[2]瓮占平.钾离子通道与肿瘤关系研究进展.国际病理科学与临床杂志, 2005, 25(6):488-491.
[3] Patel AJ, Lazdunski M. The 2P-domain K+ channels: role in apoptosis and tumorigenesis. Pflugers Arch - Eur J Physiol, 2004, (448):261–273.
[4] Mu D, Chen L, Zhang X, et al. Genomic amplification and oncogenic properties of the KCNK9 potassium channel gene. Cancer Cell, 2003, 3(3):297-302.
[5] Lin Pei, Ofer Wiser, Anthony Slavin, et al. Oncogenic potential of TASK3 (Kcnk9) depends on K+ channel function. PNAS, 2003, 100(13):7803-7807.
[6] Ouadid - Ahidouch H, Chaussade F, Roudbaraki M, et al. Kv1. 1 K+ channels identification in human breast carcinoma cells: involvement in cell proliferation. Biochem Biophys Res Commun, 2000, (278):272–277.
[7] Ouadid-Ahidouch H, RoudbarakiM, Ahidouch A, et al. Cell - cycle - dependent expression of the large Ca2+ -activated K+ channels in breast cancer cells. Biochem Biophys Res Commun, 2004, 316(1):244-251.
[8] Ouadid-Ahidouch H, RoudbarakiM, et al. Functional and molecular identification of intermediate-conductance Ca 2+-activated K_ channels in breast cancer cells: association with cell cycle progression. Am J Physiol Cell Physiol, 2004, (287): C125–C134.
[9] Potier M, Joulin V, Roger S, et al. Identification of SK3 channel as a new mediator of breast cancer cell migration. Mol Cancer Ther, 2006, 5(11):2946-2953.
[10] Stringer BK, Cooper AG, Shepard SB. Overexpression of the G-protein inwardly rectifying potassium channel 1 (GIRK1) in primary breast carcinomas correlates with axillary lymph node metastasis. Cancer Res, 2001, 61(2):582-588.
[11] Lisanti MP, Scherer PE, Tang Z, et al. Caveolae, caveolin and caveolin-rich membrane domains: a signaling hypothesis. Trends Cell Biol, 1994, 4: 231–235.
[12] Ange Maguy, Terence E. Hebert ,Stanley Nattel, et al. Involvement of lipid rafts and caveolae in cardiac ion channel function.Cardiores, 2006, 69:798– 807.
[13] Angel Cogolludo, Laura Moreno, Federica Lodi, et al. Serotonin Inhibits Voltage-Gated K+ Currents in Pulmonary Artery Smooth Muscle Cells: Role of 5-HT2A Receptors, Caveolin-1, and KV1.5 Channel Internalization. Circ. Res, published online Mar 9, 2006.
[14] Jürgen F.Heubach, Eva M.Graf, Judith Leutheuser, et al. Electrophysiological properties of human mesenchymal stem cells. J Physiol, 2003, 554(3) 659-672.
[15] Amanda B. Mackenzie, Hari Chirakkal, R. Alan North, et al. Kv1.3 potassium channels in human alveolar macrophages. Am J Physiol Lung Cell Mol Physiol, 2003, 285: 862 -868.
[16] Gregory R. Wade, Lisanne G. Laurier, Harold G. Preiksaitis, et al. Delayed rectifier and Ca2+-dependent K+currents in human esophagus: roles in regulating muscle contraction. Am J Physiol Gastrointest Liver Physiol, 1999, 277:885-895.
[17] Preussat K, Beetz C, Schrey M, et al. Expression of voltage-gated potassium channels Kv1.3 and Kv1.5 in human gliomas. Neurosci Lett , 2003,346:33-36.
[18] Wang Z. Roles of K+ channels in regulating tumour cell proliferation and apoptosis. Pflugers Arch , 2004 , 448(3) :274.
[19] Razani B, Woodman SE, Lisanti MP. Caveolae: from cell biology to animal physiology.Pharmacol Rev, 2002, 54: 431–467.
[20] Lisanti MP, Scherer PE, Tang Z, et al. Caveolae, caveolin and caveolin-rich membrane domains: a signaling hypothesis. Trends Cell Biol, 1994, 4: 231–235.
[21] Abdul M, Santo A, Hoosein N. Activity of potassium channel-blockers in breast cancer. Anticancer Res, 2003, 23(4): 3347-3351.
[22] Adam M. Brainard, Andrea J. Miller, Jeffrey R. Martens, et al. Maxi-K channels localize to caveolae in human myometrium: a role for an actin-channel-caveolin complex in the regulation of myometrial smooth muscle K+ current. Am J Physiol Cell Physiol, 2005, 289: C49–C57.
[23] Taylor B. Guo,Jiawei Lu,1 Tie Li, et al.Insulin-activated, K+- channel–sensitive Akt pathway is primary mediator of ML-1 cell proliferation. Am J Physiol Cell Physiol. 2005, 289:257-263.
[24] Thorborn J, Frost JA, Thorborn A. Mitogen-activated protein kinases mediate changes in gene expression, but not cytoskeletal organization associated with cardiac muscle cell hypertrophy. J Cell Biol, 1994, 126:1565–1572.
[1] Lisanti MP, Scherer PE, Tang Z, et al. Caveolae, caveolin and caveolin-rich membrane domains: a signaling hypothesis. Trends Cell Biol, 1994, 4: 231–235.
[2] Cano E, Mahadevan LC. Parallel signal processing among mammalian MAPKs. TIBS, 1995, 20:117.
[3] Abe JI, Kusuhara M, Ulevitch RJ et al. Big mitogen-activated protein kinase 1(BMK1)is a redox-sensitive kinase. J Biol Chem,1996,271(28):165-186.
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[5] Wondergem R, Cregan M, Strikler L, et al. Membrane potassium channels and human bladder tumor cells. II. Growth properties. J Membr Biol, 1998, 161:257–262.
[6] Lepple WA, Berweck S, Bohmig M, et al. K+ channels and the intracellular calcium signal in human melanoma cell proliferation. J Membr Biol, 1996, 151:149–157.
[7] Satoko Tahara, Keiichi Fukuda, Hiroaki Kodama, et al. Potassium Channel Blocker Activates Extracellular Signal-Regulated Kinases Through Pyk2 and Epidermal Growth Factor Receptor in Rat Cardiomyocytes. J. Am. Coll. Cardiol. 2001, 38: 1554- 1563.
[8]韩维娜,刘晔,吕昌莲,等. ERK1 /2通路在42AP诱导大鼠肺动脉收缩中的作用.中国药理学通报, 2007, 23 (2) : 202～206.
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[2] Scott P. Fraser, James K.J.Diss, Athina-Myrto Chioni, et al. Voltage-Gated Sodium Channel Expression and Potentiation of Human Breast Cancer Metastasis. Clin Cancer Res, 2005,11: 5381– 5389.
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[6] Patel AJ, Lazdunski M. The 2P-domain K+ channels: role in apoptosis and tumorigenesis. Pflugers Arch - Eur J Physiol, 2004, (448):261–273.
[7] Mu D, Chen L, Zhang X, et al. Genomic amplification and oncogenic properties of the KCNK9 potassium channel gene. Cancer Cell, 2003, 3(3):297-302.
[8] Lin Pei, Ofer Wiser, Anthony Slavin, et al. Oncogenic potential of TASK3 (Kcnk9)depends on K+ channel function. PNAS, 2003, 100(13):7803-7807.
[9] Luis A.Pardo, Donato del Camino, Araceli Sánchez, et al. Oncogenic potential of EAG K+ channels. EMBO, 1999, 18(20):5540-5547.
[10] Ouadid-Ahidouch H, Chaussade F, Roudbaraki M, et al. Kv1. 1 K+ channels identi- fication in human breast carcinoma cells: involvement in cell proliferation. Biochem Biophys Res Commun, 2000, (278):272–277.
[11] Abdul M, Santo A, Hoosein N. Activity of potassium channel-blockers in breast cancer. Anticancer Res, 2003, 23(4): 3347-3351.
[12] Ouadid-Ahidouch H, RoudbarakiM, Ahidouch A, et al. Cell - cycle - dependent expression of the large Ca2+ -activated K+ channels in breast cancer cells. Biochem Biophys Res Comm un, 2004, 316(1):244-251.
[13] Roger S, Potier M, Vandier C, et al. Description and role in proliferation of iberiotoxin-sensitive currents in different human mammary epithelial normal and cancerous cells. Biochim Biophys Acta, 2004, 1667(2):190-199.
[14] Ouadid-Ahidouch H, RoudbarakiM, et al.Functional and molecular identification of intermediate-conductance Ca 2+-activated K_ channels in breast cancer cells: association with cell cycle progression. Am J Physiol Cell Physiol, 2004, (287): C125–C134.
[15] Woodfork KA, Wonderlin WF, Peterson VA, et al. Inhibition of ATP-sensitive potassium channels causes reversible cell-cycle arrest of human breast cancer cells in tissue culture. J Cell Physiol, 1995, 162(2):163-171.
[16] Wonderlin WF, Woodfork KA, Strobl JS, et al. Changes in membrane potential during the progression of MCF-7 human mammary tumor cells through the cell cycle.J Cell Physiol, 1995, 165(1):177-185.
[17] Klimatcheva E, Wonderlin WF. An ATP-sensitive K+ current that regulates progression through early G1 phase of the cell cycle in MCF-7 human breast cancer cells. J Membr Biol, 1999, 171(1): 35-46.
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[21] Borowiec AS, Hague F, Harir N, et al. IGF-1 activates hEAG K(+) channels through an Akt-dependent signaling pathway in breast cancer cells: Role in cell proliferation. J Cell Physiol, 2007, 212(3):690-701.
[22] Potier M, Joulin V, Roger S, et al. Identification of SK3 channel as a new mediator of breast cancer cell migration. Mol Cancer Ther, 2006, 5(11):2946-2953.
[23] Stringer BK, Cooper AG, Shepard SB. Overexpression of the G-protein inwardly rectifying potassium channel 1 (GIRK1) in primary breast carcinomas correlates with axillary lymph node metastasis. Cancer Res, 2001, 61(2):582-588.
[24] Plummer HK 3rd, Yu Q, Cakir Y, et al. Expression of inwardly rectifying potassium channels (GIRKs) and beta-adrenergic regulation of breast cancer cell. http://www.biomedcentral.com,2004-12-06.
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[26]张勇,杨安钢,周士胜,氯离子通道家族研究进展.医学分子生物学杂志. 2004, 1 (4):245-248.
[27] Achim D. Gruber, Bendicht U. Pauli. Tumorigenicity of Human Breast Cancer Is Associated with Loss of the Ca2+- activated Chloride Channel CLCA2. Cancer Research, 1999, 59:5488–5491.
[28] Janel R. Beckley, Bendicht U. Pauli, Randolph C. Elble. Re-expression of Detachment- inducible Chloride Channel mCLCA5 Suppresses Growth of Metastatic Breast Cancer Cells. J Biological Chemistry, 2004, 279(40), 41634–41641.
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[31] Roger S, Besson P, Le Guennec JY. Involvement of a novel fast inward sodium current in the invasion capacity of a breast cancer cell line. Biochim Biophys Acta, 2003, 1616(2): 107-111.
[32] Roger S, Le Guennec JY, Besson P. Particular sensitivity to calcium channel blockers of the fast inward voltage-dependent sodium current involved in the invasive properties of a metastastic breast cancer cell line. Br J Pharmacol. 2004, 141(4):610-615.
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[1]张洪,邹伟. Caveolin-1与乳腺癌关系的研究进展.生物化学与分子生物学报,2007, 23(1):23-26.
[2] Achim D. Gruber, Bendicht U. Pauli. et al. Tumorigenicity of Human Breast Cancer Is Associated with Loss of the Ca2+- activated Chloride Channel CLCA2. Cancer Research, 1999, 59:5488–5491.
[3] Bo Skaaning Jensen, Niels ?dum, Nanna Koschmieder J?rgensen, et al. Inhibition of T cell proliferation by selective block of Ca2+-activated K+ channels. PNAS, 1999, 96: 10917 - 10921.
[4] A Lepple-Wienhues, S Berweck, M Bohmig, et al. K+ channels and the intracellular calcium signal in human melanoma cell proliferation. J Membr Biol, 1996, 151(2): 149- 157.
[5] Wonderlin WF, Woodfork KA, Strobl JS, et al. Changes in membrane potential during the progression of MCF-7 human mammary tumor cells through the cell cycle. J Cell Physiol, 1995, 165(1):177-185.
[6] RN Skryma, NB Prevarskaya, L Dufy-Barbe, et al. Potassium conductance in the androgen-sensitive prostate cancer cell line, LNCaP: involvement in cell proliferation. Prostate, 1997, 33(2): 112-122.
[7] SG Rane. The growth regulatory fibroblast IK channel is the prominent electro- physiological feature of rat prostatic cancer cells. Biochem Biophys Res Commun, 2000, 269(2): 457-63.
[8] Laura Bianchi, Barbara Wible, Annarosa Arcangeli, et al. Herg Encodes a K+ Current Highly Conserved in Tumors of Different Histogenesis: A Selective Advantage for Cancer Cells? Cancer Research, 1998, 58:815-822.
[9] LA Pardo, D del Camino, A Sanchez, et al. Oncogenic potential of EAG K+ channels. EMBO J, 1999, 18(20): 5540-5547.
[10] Hayashi K, Matsuda S, Machida K. Invasion Activating Caveolin-1 Mutation in Human Scirrhous Breast Cancers. Cancer Res, 2001, 61: 2361-2364.
[11] Zou W, Mcdaneld L.and Smith LM. Caveolin-1 Haploinsufficiency leads to partial transformation of human breast epithelialcells. Anticancer Res, 2003, 23 (6C): 4581 -4586.
[12]张洪,邹伟. Caveolin-1与乳腺癌关系的研究进展.生物化学与分子生物学报, 2007,23(1):23-26.
[13] Ouadid- Ahidouch H, Chaussade F, Roudbaraki M, et al. Kv1. 1 K+ channels identification in human breast carcinoma cells: involvement in cell proliferation. Biochem Biophys Res Commun, 2000, 278:272–277.
[14] Abdul M, Santo A, Hoosein N. Activity of potassium channel-blockers in breast cancer. Anticancer Res, 2003, 23(4): 3347-3351.
[15] L Guo, ZS Li, HL Wang, et al. Carboxyamido-triazole inhibits proliferation of human breast cancer cells via G(2)/M cell cycle arrest and apoptosis. Eur J Pharmacol, 2006, 538(1-3):15-22.
[16] S Roger, P Besson, JY Le Guennec. Involvement of a novel fast inward sodium current in the invasion capacity of a breast cancer cell line. Biochim Biophys Acta, 2003, 1616(2): 107-111.
[17]张勇,杨安钢.周士胜,氯离子通道家族研究进展.医学分子生物学杂志. 2004, 1 (4) :245-248.
[18]田晶,周士胜,陶凌,胡玉珍. NPPB对肝癌细胞增殖的影响.第四军医大学吉林军医学院学报. 2003, 25(2):63-65
[19]马建军,周士胜,保庭毅,等.氯通道阻断剂NPPB对肾癌细胞系GRC-1生长的抑制作用.第四军医大学学报, 2003, 09: 822～824
[20]瓮占平.钾离子通道与肿瘤关系研究进展.国际病理科学与临床杂志, 2005,25(6):488-491.
[21] Scott P. Fraser, James K.J.Diss, Athina-Myrto Chioni. Voltage-Gated Sodium Channel Expression and Potentiation of Human Breast Cancer Metastasis. Clin Cancer Res . 2005, 11(15): 5381– 5389.
[1] Wang Z. Roles of K+ channels in regulating tumour cell proliferation and apoptosis. Pflugers Arch, 2004, 448 (3): 274-286.
[2]瓮占平.钾离子通道与肿瘤关系研究进展.国际病理科学与临床杂志, 2005, 25(6):488-491.
[3] Patel AJ, Lazdunski M. The 2P-domain K+ channels: role in apoptosis and tumorigenesis. Pflugers Arch - Eur J Physiol, 2004, (448):261–273.
[4] Mu D, Chen L, Zhang X, et al. Genomic amplification and oncogenic properties of the KCNK9 potassium channel gene. Cancer Cell, 2003, 3(3):297-302.
[5] Lin Pei, Ofer Wiser, Anthony Slavin, et al. Oncogenic potential of TASK3 (Kcnk9) depends on K+ channel function. PNAS, 2003, 100(13):7803-7807.
[6] Ouadid - Ahidouch H, Chaussade F, Roudbaraki M, et al. Kv1. 1 K+ channels identification in human breast carcinoma cells: involvement in cell proliferation. Biochem Biophys Res Commun, 2000, (278):272–277.
[7] Ouadid-Ahidouch H, RoudbarakiM, Ahidouch A, et al. Cell - cycle - dependent expression of the large Ca2+ -activated K+ channels in breast cancer cells. Biochem Biophys Res Commun, 2004, 316(1):244-251.
[8] Ouadid-Ahidouch H, RoudbarakiM, et al. Functional and molecular identification of intermediate-conductance Ca 2+-activated K_ channels in breast cancer cells: association with cell cycle progression. Am J Physiol Cell Physiol, 2004, (287): C125–C134.
[9] Potier M, Joulin V, Roger S, et al. Identification of SK3 channel as a new mediator of breast cancer cell migration. Mol Cancer Ther, 2006, 5(11):2946-2953.
[10] Stringer BK, Cooper AG, Shepard SB. Overexpression of the G-protein inwardly rectifying potassium channel 1 (GIRK1) in primary breast carcinomas correlates with axillary lymph node metastasis. Cancer Res, 2001, 61(2):582-588.
[11] Lisanti MP, Scherer PE, Tang Z, et al. Caveolae, caveolin and caveolin-rich membrane domains: a signaling hypothesis. Trends Cell Biol, 1994, 4: 231–235.
[12] Ange Maguy, Terence E. Hebert ,Stanley Nattel, et al. Involvement of lipid rafts and caveolae in cardiac ion channel function.Cardiores, 2006, 69:798– 807.
[13] Angel Cogolludo, Laura Moreno, Federica Lodi, et al. Serotonin Inhibits Voltage-Gated K+ Currents in Pulmonary Artery Smooth Muscle Cells: Role of 5-HT2A Receptors, Caveolin-1, and KV1.5 Channel Internalization. Circ. Res, published online Mar 9, 2006.
[14] Jürgen F.Heubach, Eva M.Graf, Judith Leutheuser, et al. Electrophysiological properties of human mesenchymal stem cells. J Physiol, 2003, 554(3) 659-672.
[15] Amanda B. Mackenzie, Hari Chirakkal, R. Alan North, et al. Kv1.3 potassium channels in human alveolar macrophages. Am J Physiol Lung Cell Mol Physiol, 2003, 285: 862 -868.
[16] Gregory R. Wade, Lisanne G. Laurier, Harold G. Preiksaitis, et al. Delayed rectifier and Ca2+-dependent K+currents in human esophagus: roles in regulating muscle contraction. Am J Physiol Gastrointest Liver Physiol, 1999, 277:885-895.
[17] Preussat K, Beetz C, Schrey M, et al. Expression of voltage-gated potassium channels Kv1.3 and Kv1.5 in human gliomas. Neurosci Lett , 2003,346:33-36.
[18] Wang Z. Roles of K+ channels in regulating tumour cell proliferation and apoptosis. Pflugers Arch , 2004 , 448(3) :274.
[19] Razani B, Woodman SE, Lisanti MP. Caveolae: from cell biology to animal physiology.Pharmacol Rev, 2002, 54: 431–467.
[20] Lisanti MP, Scherer PE, Tang Z, et al. Caveolae, caveolin and caveolin-rich membrane domains: a signaling hypothesis. Trends Cell Biol, 1994, 4: 231–235.
[21] Abdul M, Santo A, Hoosein N. Activity of potassium channel-blockers in breast cancer. Anticancer Res, 2003, 23(4): 3347-3351.
[22] Adam M. Brainard, Andrea J. Miller, Jeffrey R. Martens, et al. Maxi-K channels localize to caveolae in human myometrium: a role for an actin-channel-caveolin complex in the regulation of myometrial smooth muscle K+ current. Am J Physiol Cell Physiol, 2005, 289: C49–C57.
[23] Taylor B. Guo,Jiawei Lu,1 Tie Li, et al.Insulin-activated, K+- channel–sensitive Akt pathway is primary mediator of ML-1 cell proliferation. Am J Physiol Cell Physiol. 2005, 289:257-263.
[24] Thorborn J, Frost JA, Thorborn A. Mitogen-activated protein kinases mediate changes in gene expression, but not cytoskeletal organization associated with cardiac muscle cell hypertrophy. J Cell Biol, 1994, 126:1565–1572.
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