RLIP76在肿瘤靶向治疗的研究进展
Research Progress of RLIP76 in Targeted Therapy of Tumor
DOI: 10.12677/ACM.2019.98149, PDF,   
作者: 刘 东, 毛 艺, 马雅楠, 岳少宇：蚌埠医学院，临床医学院，安徽 蚌埠
关键词: RLIP76；肿瘤；靶向治疗；转运；凋亡；RLIP76； Tumor； Targeted Therapy； Transport； Apoptosis
摘要: 过去20年里，全球癌症发病率处于快速上升阶段，癌症的治疗一直是医学界的难题。目前常规化疗药物的主要缺点是选择性较低，对肿瘤的治疗效果较差。具有高度特异性的靶向治疗对患者的治疗效果更好，不良反应更少。靶向治疗的开发具有良好的前景。RLIP76是一种多药转运体和抗凋亡蛋白，是化疗耐药和癌细胞信号转导的关键分子之一。RLIP76在癌细胞中存在固有的过度表达，而正常细胞对RLIP76的依赖性相对较小，这为认识RLIP76作为一种独特的抗癌靶点的潜力提供了证据。在许多癌细胞系和异种移植物中，通过抑制RLIP76触发凋亡通路，一致观察到的退化结果为RLIP76在临床上作为一种新的治疗药物提供了一定的思路。
Abstract: In the past 20 years, the global incidence of cancer has been rising rapidly and the treatment of cancer has always been a challenge for the medical community. At present, the main shortcomings of conventional chemotherapy drugs are low selectivity and poor therapeutic effect on tumors. Targeted therapy with high specificity has a better therapeutic effect on patients with fewer ad-verse reactions. The development of targeted therapy has a good prospect. RLIP76 is a multidrug transporter and anti-apoptotic protein, which is one of the key molecules in chemotherapy re-sistance and signal transduction of cancer cells. RLIP76 is inherently overexpressed in cancer cells, while normal cells have relatively little dependence on RLIP76, which provides evidence for ac-knowledging RLIP76’s potential as a unique anticancer target. In many cancer cell lines and xeno-grafts, by inhibiting RLIP76 to trigger the apoptotic pathway, the consistently observed degradation results provide some ideas for RLIP76 as a new therapeutic drug in clinical practice.
文章引用：刘东, 毛艺, 马雅楠, 岳少宇. RLIP76在肿瘤靶向治疗的研究进展[J]. 临床医学进展, 2019, 9(8): 978-985. https://doi.org/10.12677/ACM.2019.98149

参考文献

[1] Wurtzel, J.G., Lee, S., Singhal, S.S., et al. (2015) RLIP76 Regulates Arf6-Dependent Cell Spreading and Migration by linking ARNO with Activated R-R as at Recycling Endosomes. Biochemical and Biophysical Research Communications, 467, 785-791. [Google Scholar] [CrossRef] [PubMed]
[2] https://asia.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000017797;r=18:9475009-9538114
[3] Awasthi, S., Cheng, J., Singhal, S.S., Saini, M.K., Pandya, U., Pikula, S., et al. (2000) Novel Function of Human RLIP76: ATP-Dependent Transport of Glutathione-Conjugates and Doxorubicin. Biochemistry, 39, 9327-9334. [Google Scholar] [CrossRef] [PubMed]
[4] Awasthi, S., Singhal, S.S., et al. (2008) RLIP76 and Cancer. Clinical Cancer Research, 14, 4372-4377. [Google Scholar] [CrossRef] 
[5] Wang, Q., Wang, J.Y., Zhang, X.P., Lv, Z.W., Fu, D., Lu, Y.C., et al. (2013) RLIP76 Is over-Expressed in Human Glioblastomas and Is Required for Proliferation, Tumorigenesis and Suppression of Apoptosis. Carcinogenesis, 34, 916-926. [Google Scholar] [CrossRef] [PubMed]
[6] Wang, Q., Qian, J., Wang, J.Y., Luo, C., Chen, J., Hu, G., et al. (2013) Knockdown of RLIP76 Expression by RNA Interference Inhibits Invasion, Induces Cell Cycle Arrest, and Increases Chemosensitivity to the Anticancer Drug Temozolomide in Glioma Cells. Journal of Neuro-Oncology, 112, 73-82. [Google Scholar] [CrossRef] [PubMed]
[7] Wang, W., Liu, J., Qi, J., et al. (2016) Downregulation of RLIP76 Is Associated with Vincristine Resistance in Human Colorectal Cancer HCT-8/VCR Cells. International Journal of Oncology, 49, 1505-1512. [Google Scholar] [CrossRef] [PubMed]
[8] Singhal, S.S., Awasthi, Y.C. and Awasthi, S. (2006) Regression of Melanoma in a Murine Model by RLIP76 Depletion. Cancer Research, 66, 2354-2360. [Google Scholar] [CrossRef] 
[9] Singhal, S.S., Yadav, S., Drake, K., Singhal, J. and Awas-thi, S. (2008) Hsf-1 and POB1 Induce Drug-Sensitivity and Apoptosis by Inhibiting Ralbp1. Journal of Biological Chemistry, 283, 19714-19729. [Google Scholar] [CrossRef] 
[10] Cheng, J., Sharma, R., Yang, Y., et al. (2001) Accelerated Metabo-lism and Exclusion of 4-Hydroxy-Nonenal through Induction of RLIP76 and hGST5.8 Is an Early Adaptive Response of Cells to Heat and Oxidative-Stress. Journal of Biological Chemistry, 276, 41213-41223. [Google Scholar] [CrossRef] 
[11] Awasthi, S., Singhal, S.S., Yadav, S., Singhal, J., Drake, K., Nadkar, A., et al. (2005) RLIP76 Is a Major Determinant of Radiation-Sensitivity. Cancer Research, 65, 6022-6028. [Google Scholar] [CrossRef] 
[12] Awasthi, S., Hallene, K.L., Fazio, V., Singhal, S.S., Cu-cullo, L., Awasthi, Y.C., et al. (2005) RLIP76, a Non-ABC Transporter, and Drug Resistance in Epilepsy. BMC Neu-roscience, 6, 61. [Google Scholar] [CrossRef] [PubMed]
[13] Awasthi, S., Singhal, S.S., Sharma, R., Zimniak, P. and Awasthi, Y.C. (2003) Transport of Glutathione-Conjugates and Chemotherapeutic Drugs by RLIP76: A Novel Link between G-Protein and Tyrosine-Kinase Signaling and Drug-Resistance. International Journal of Cancer, 106, 635-646. [Google Scholar] [CrossRef] [PubMed]
[14] Awasthi, S., Cheng, J., Singhal, S.S., Sharma, R., Pandya, U., Singh, S.V., et al. (2001) Functional Reassembly of Xenobiotic-Transport from the N-Terminal and C-Terminal Domains of RLIP76 and Identification of ATP-Binding Sequences. Biochemistry, 40, 4159-4168. [Google Scholar] [CrossRef] [PubMed]
[15] Singhal, J., Singhal, S.S., Yadav, S., Warnke, M., Yacoub, A., Dent, P., et al. (2008) RLIP76 in Defense of Radiation and Chemical-Poisoning. International Journal of Radiation Oncology, Bi-ology, Physics, 72, 553-561. [Google Scholar] [CrossRef] [PubMed]
[16] Singhal, S.S., Yadav, S., Singhal, J., Sahu, M., Sehrawat, A. and Awasthi, S. (2008) Diminished Drug Transport and Augmented Radiation Sensitivity Caused by Loss of RLIP76. FEBS Letters, 582, 3408-3414. [Google Scholar] [CrossRef] [PubMed]
[17] Singhal, S.S., Singhal, J., Figarola, J., Horne, D. and Awasthi, S. (2015) RLIP76 Targeted Therapy for Kidney Cancer. Pharmaceutical Research, 32, 3123-3136. [Google Scholar] [CrossRef] [PubMed]
[18] Hu, Y. and Mivechi, N.F. (2003) HSF-1 Interacts with Ral-Binding-Protein 1 in a Stress-Responsive, Multi-Protein Complex with HSP90 in Vivo. Journal of Biological Chemistry, 278, 17299-17306. [Google Scholar] [CrossRef] 
[19] Singhal, S.S., Yadav, S., Drake, K., Singhal, J. and Awasthi, S. (2008) Hsf-1 and POB1 Induce Drug-Sensitivity and Apoptosis by Inhibiting Ralbp1. Journal of Biological Chemistry, 283, 19714-19729. [Google Scholar] [CrossRef] 
[20] Singhal, S.S. and Awasthi, S. (2006) Glutathione-Conjugate Transport and Stress-Response Signaling: Role of RLIP76. In: Awasthi, S., Ed., Toxicology of Glutathione S-Transferases, CRC Press, Boca Raton, FL, 231-256.
[21] Vatsyayan, R. and Chaudhary, P. (2009) Role of RLIP76 in Doxorubicin Resistance in Lung Cancer. International Journal of Oncology, 34, 1505-1511. [Google Scholar] [CrossRef] [PubMed]
[22] Awasthi, S., Sharma, R., Singhal, S.S., Zimniak, P. and Awasthi, Y.C. (2002) RLIP76, a Novel Transporter Catalyzing ATP-Dependent Efflux of Xenobiotics. Drug Metabolism & Disposition, 30, 1300-1310. [Google Scholar] [CrossRef] [PubMed]
[23] 郭晓峰, 刘高峰, 李保田, 杨鲲鹏, 张勇, 刘艳, 李丹丹, 李东方, 崔素娟. RLIP76和VEGF在食管鳞癌组织中的表达及临床意义[J]. 临床肿瘤学杂志, 2018, 23(4): 330-334.
[24] 潘海霞, 白义凤, 胡洪林. RLIP76在调节小细胞肺癌多药耐药中的作用及临床意义[J]. 中华肿瘤杂志, 2015, 37(4): 266-271.
[25] Wang, W., Liu, J., Qi, J., et al. (2016) RLIP76 Increases Apoptosis through Akt/mTOR Signaling Pathway in Gastric Cancer. Oncology Reports, 36, 2216-2224. [Google Scholar] [CrossRef] [PubMed]
[26] Wang, C.Z., Yuan, P., Xu, B., et al. (2015) RLIP76 Expression as a Prognostic Marker of Breast Cancer. European Review for Medical and Pharmacological Sciences, 19, 2105-2111.
[27] Singhal, S.S., Sehrawat, A., Metha, A., Sahu, M. and Awasthi, S. (2009) Functional Reconstitution of RLIP76 Catalyzing ATP-Dependent Transport of Glutathione-Conjugate. International Journal of Oncology, 34, 191-199.
[28] Singhal, S.S., Singhal, J., Yadav, S., Dwivedi, S., Boor, P., Awasthi, Y.C., et al. (2007) Regression of Lung and Colon Cancer Xenografts by Depleting or Inhibiting RLIP76. Cancer Research, 67, 4382-4389. [Google Scholar] [CrossRef] 
[29] Singhal, S.S., Roth, C., Leake, K., Singhal, J., Yadav, S. and Awasthi, S. (2009) Regression of Prostate Cancer Xenografts by RLIP76 Depletion. Biochemical Pharmacology, 77, 1074-1083. [Google Scholar] [CrossRef] [PubMed]
[30] Vatsyayan, R. and Rao Lelsani, P.C. (2010) RLIP76: A Versatile Transporter and an Emerging Target for Cancer Therapy. Biochemical Pharmacology, 79, 1699-1705. [Google Scholar] [CrossRef] [PubMed]
[31] Yadav, S., Singhal, S.S., Singhal, J., Wickramarachchi, D., Kuntson, E., Albrecht, T.B., et al. (2004) Identification of Membrane-Anchoring Domains of RLIP76 Using Deletion Mutants Analyses. Biochemistry, 43, 16243-16253. [Google Scholar] [CrossRef] [PubMed]
[32] Choudhuri, S. and Klaassen, C.D. (2006) Structure, Function, Expression, Genomic Organization, and Single Nucleotide-Polymorphisms of Human ABCB1 (MDR1), ABCC (MRP), and ABCG2 (BCRP) Efflux Transporters. International Journal of Toxicology, 25, 231-259. [Google Scholar] [CrossRef] [PubMed]
[33] Higgins, C.F. (2007) Multiple Molecular Mechanisms for Mul-tidrug-Resistance Transporters. Nature, 446, 749-757. [Google Scholar] [CrossRef] [PubMed]
[34] Sharom, F.J. (2008) ABC Multidrug-Transporters: Structure, Function and Role in Chemo-Resistance. Pharmacogenomics, 9, 105-127. [Google Scholar] [CrossRef] [PubMed]
[35] Singhal, S.S., Sehrawat, A., Sahu, M., Singhal, P., Vatsyayan, R., Lelsani, P.C., et al. (2010) RLIP76 Transports Sunitinib and Sorafenib and Mediates Drug Resistance in Kidney Cancer. International Journal of Cancer, 126, 1327-1338. [Google Scholar] [CrossRef] [PubMed]

为你推荐