摘要
如今，癌症治疗方法面临的最大挑战之一就是成功找到选择性目标。 前列腺细胞凋亡反应-4（Par-4）是一种选择性肿瘤抑制蛋白，由于其对诱导癌细胞凋亡的特异性而具有令人感兴趣的治疗潜力。 Par-4活性和水平可以在几种肿瘤和癌细胞类型中下调，表明预后不良和治疗抗性。 已经研究了增加Par-4表达水平的努力，包括通过用腺病毒载体或质粒转染将其用作治疗性蛋白质。 然而，基因治疗非常复杂，仍然存在许多需要克服的障碍。 我们决定审查具有上调Par-4能力的分子和药物，从而成为达到这一药物治疗目标的替代方案。 此外，Par-4的定位和功能在一些癌症中得到了回顾，阐明了它如何用作治疗靶点。
关键词: 前列腺细胞凋亡反应-4，治疗创新，肿瘤抑制蛋白，治疗靶，治疗蛋白，Par-4定位。
图形摘要
[1]
Sells S, Wood DP, Joshi-barve SS, et al. Commonality of apoptosis of the gene programs in androgen-dependent prostate cells1 induced and by effectors. Cell Growth Differ 1994; 5: 457-66.
[2]
Sells SF, Han SS, Muthukkumar S, et al. Expression and function of the leucine zipper protein par-4 in apoptosis. Mol Cell Biol 1997; 17(7): 3823-32.
[3]
Zhao Y, Rangnekar VM. Apoptosis and Tumor Resistance Conferred by Par-4. Cancer Biol Ther 2008; 7(2): 1867-74.
[4]
Johnstone RW, Tommerup N, Hansen C, Vissing H, Shi Y. Mapping of the Human PAWR (Par-4) Gene to Chromosome 12q21. Genomics 1998; 53(2): 241-3.
[5]
El-Guendy N, Zhao Y, Gurumurthy S, Burikhanov R, Rangnekar VM. Identification of a unique core domain of par-4 sufficient for selective apoptosis induction in cancer cells. Mol Cell Biol 2003; 23(16): 5516-25.
[6]
Hebbar N, Wang C, Rangnekar VM. Mechanisms of apoptosis by the tumor suppressor par-4. J Cell Physiol 2012; 227(12): 3715-21.
[7]
Goswami A, Ranganathan P, Rangnekar VM. The phosphoinositide 3-kinase/akt1/par-4 axis: a cancer-selective therapeutic target. Cancer Res 2006; 66(6): 2889-92.
[8]
Cook J, Krishnan S, Ananth S, et al. Decreased expression of the pro-apoptotic protein par-4 in renal cell carcinoma. Oncogene 1999; 18(5): 1205-8.
[9]
Moreno-Bueno G, Fernandez-Marcos PJ, et al. Inactivation of the candidate tumor suppressor par-4 in endometrial cancer. Cancer Res 2007; 67(5): 1927-34.
[10]
Kögel D, Reimertz C, Mech P, et al. Dlk/ZIP kinase-induced apoptosis in human medulloblastoma cells: requirement of the mitochondrial apoptosis pathway. Br J Cancer 2001; 85(11): 1801-8.
[11]
Nagai MA, Gerhard R, Salaorni S, et al. Down-regulation of the candidate tumor suppressos gene par-4 gene with poor prognosis in breast cancer. Int J Oncol 2010; 37: 41-9.
[12]
Boehrer S, Chow KU, Beske F, et al. In lymphatic cells par-4 sensitizes to apoptosis by down-regulating bcl-2 and promoting disruption of mitochondrial membrane potential and caspase activation. Cancer Res 2002; 62(6): 1768-75.
[14]
Qiu G, Ahmed M, Sells SF, et al. Mutually exclusive expression patterns of Bcl-2 and Par-4 in human prostate tumors consistent with down-regulation of Bcl-2 by Par-4. Oncogene 1999; 18(3): 623-31.
[15]
Huang YT, Chueh SC, Teng CM, Guh JH. Investigation of ouabain-induced anticancer effect in human androgen-independent prostate cancer PC-3 Cells. Biochem Pharmacol 2004; 67(4): 727-33.
[16]
Srinivasan S, Ranga RS, Burikhanov R, Han SS, Chendil D. Par-4-dependent apoptosis by the dietary compound withaferin A in prostate cancer cells. Cancer Res 2007; 67(1): 246-53.
[17]
Das TP, Suman S, Alatassi H, Ankem MK, Damodaran C. Inhibition of AKT promotes FOXO3a-dependent apoptosis in prostate cancer. Cell Death Dis 2016; 7(2): 2111-10.
[18]
Suman S, Das TP, Moselhy J, Pal D, Kolluru V. Oral administration of withaferin a inhibits carcinogenesis of prostate in TRAMP model. Oncotarget 2016; 7(33): 1-11.
[19]
Moselhy J, Suman S, Alghamdi M. Withaferin a inhibits prostate carcinogenesis in a PTEN-Deficient mouse model of prostate cancer. Neoplasia (United States) 2017; 19(6): 451-9.
[20]
MacLean MA, Scott BE, Deziel BA. North american cranberry (Vaccinium Macrocarpon) stimulates apoptotic pathways in DU145 human prostate cancer cells in vitro. Nutr Cancer 2011; 63(1): 109-20.
[21]
Roumeliotis TI, Halabalaki M, Alexi X, Ankrett D. Pharmacoproteomic study of the natural product ebenfuran III in DU-145 prostate cancer cells: The quantitative and temporal interrogation of chemically induced cell death at the protein level. J Proteome Res 2013; 12(4): 1591-603.
[22]
Brasseur K, Auger P, Asselin E, et al. Parasporin-2 from a new bacillus thuringiensis 4r2 strain induces caspases activation and apoptosis in human cancer cells. PLoS One 2015; 10(8): 1-22.
[23]
Sarkar S, Jain S, Rai V, et al. Plant-derived SAC domain of par-4 (prostate apoptosis response 4) exhibits growth inhibitory effects in prostate cancer cells. Front Plant Sci 2015; 6: 1-17.
[24]
Lico C, Santi L, Twym Lico C, et al. The use of plants for the production of therapeutic human peptides. Plant Cell Rep 2012; 31(3): 439-51.
[25]
Buyel JF. Plants as sources of natural and recombinant anti-cancer agents. Biotechnol Adv 2018; 36(2): 506-20.
[26]
Rossi V, Bellastella G, De Rosa C, et al. Raloxifene induces cell death and inhibits proliferation through multiple signaling pathways in prostate cancer cells expressing different levels of estrogen receptorα and β. J Cell Physiol 2011; 226(5): 1334-9.
[27]
Rah B, Amin H, Yousuf K. A novel MMP-2 inhibitor 3-azidowithaferin A (3-AzidoWA) abrogates cancer cell invasion and angiogenesis by modulating extracellular Par-4. PLoS One 2012; 7(9)
[28]
Rah B. ur Rasool R, Nayak D, et al PAWR-mediated suppression of BCL2 promotes switching of 3-azido withaferin A (3-AWA)-induced autophagy to apoptosis in prostate cancer cells. Autophagy 2015; 11(2): 314-31.
[29]
Burikhanov R, Sviripa VM, Hebbar N, et al. Arylquins target vimentin to trigger Par-4 secretion for tumor cell apoptosis. Nat Chem Biol 2014; 10(11): 924-6.
[30]
Sviripaa VM, Burikhanovc R, Obieroe JM, et al. Par-4 secretion: stoichiometry of 3-arylquinoline binding to vimentin vitaliy. Org Biomol Chem 2016; 14(1): 74-84.
[31]
Frasinyuka MS, Bondarenkob SP, Sviripac VM, et al. Development of 6H-chromeno[3,4-c]pyrido[3′,2′:4,5]thieno[2,3- e]pyridazin-6-ones as Par-4 secretagogues. Tetrahedron Lett 2015; 56(23): 3382-4.
[32]
Burikhanov R, Hebbar N, Noothi SK, et al. Chloroquine-inducible Par-4 secretion is essential for tumor cell apoptosis and inhibition of metastasis. Cell Rep 2017; 18(2): 508-19.
[33]
Hattula K, Furuhjelm J, Arffman A, Peränen J. A rab8-specific gdp/gtp exchange factor is involved in actin remodeling and polarized membrane transport. Mol Biol Cell 2002; 13(September): 3268-80.
[34]
Wang B-D, Kline CLB, Pastor DM, et al. Prostate apoptosis response protein 4 sensitizes human colon cancer cells to chemotherapeutic 5-fu through mediation of an nf kappab and microrna network. Mol Cancer 2010; 9: 98.
[35]
Zhang Z, DuBois RN. Par-4, a proapoptotic gene, is regulated by nsaids in human colon carcinoma cells. Gastroenterol 2000; 118(6): 1012-7.
[36]
He T-C, Chan TA, Vogelstein B, Kinzler KW. PPARδ is an apc-regulated target of nonsteroidal anti- inflammatory drugs. Cell 1999; 99(3): 335-45.
[37]
Chen X, Sahasrabuddhe AA, Szankasi P, et al. Fbxo45-mediated degradation of the tumor-suppressor par-4 regulates cancer cell survival. Cell Death Differ 2014; 21(10): 1535-45.
[38]
Nguyen JQ, Irby RB. TRIM21 is a novel regulator of par-4 in colon and pancreatic cancer cells. Cancer Biol Ther 2017; 18(1): 16-25.
[39]
Kline CLB, Irby RB. The pro-apoptotic protein prostate apoptosis response protein-4 (par-4) can be activated in colon cancer cells by treatment with src inhibitor and 5-FU. Apoptosis 2011; 16(12): 1285-94.
[40]
Gurumurthy S, Goswami A, Vasudevan KM, Rangnekar VM. Phosphorylation of par-4 by protein kinase a is critical for apoptosis. Mol Cell Biol 2005; 25(3): 1146-61.
[41]
Sharma AK, Kline CL, Berg A, Amin S, Irby RB. The akt inhibitor isc-4 activates prostate apoptosis response protein-4 and reduces colon tumor growth in a nude mouse model. Clin Cancer Res 2011; 17(13): 4474-83.
[42]
Sharma A, Sharma AK, Madhunapantula SV, et al. Targeting akt3 signaling in malignant melanoma using isoselenocyanates. Clin Cancer Res 2009; 15(5): 1674-85.
[43]
Kline CL, Shanmugavelandy SS, Kester M, Irby RB. Delivery of par-4 plasmid in vivo via nanoliposomes sensitizes colon tumor cells subcutaneously implanted into nude mice to 5-fu. Cancer Biol Ther 2009; 8(19): 1831-7.
[44]
Barbosa SF. da C, Costa CA, et al. aspectos epidemiológicos dos casos de leucemia e linfomas em jovens e adultos atendidos em hospital de referência para câncer em belém, estado do pará, amazônia, Brasil. Rev Pan-Amazônica Saúde 2015; 6(3): 43-50.
[45]
Brieger A, Boehrer S, Schaaf S, et al. In Bcr-abl-positive myeloid cells resistant to conventional chemotherapeutic agents, expression of par-4 increases sensitivity to imatinib (sti571) and histone deacetylase-inhibitors. Biochem Pharmacol 2004; 68(1): 85-93.
[46]
Boehrer S, Chow KU, Puccetti E, et al. Deregulated expression of prostate apoptosis response gene-4 in less differentiated lymphocytes and inverse expressional patterns of par-4 and bcl-2 in acute lymphocytic leukemia. Hematol J 2001; 2(2): 103-7.
[47]
Boehrer S, Chow KU, Ruthardt M, et al. Expression and function of prostate-apoptosis-response-gene-4 in lymphatic cells. Leuk Lymphoma 2002; 43(9): 1737-41.
[48]
Boehrer S, Nowak D, Puccetti E, et al. Prostate-apoptosis-response-gene-4 increases sensitivity to trail-induced apoptosis. Leuk Res 2006; 30(5): 597-605.
[49]
Faderl S, Kantarjian HM, Piercea S, Albitar M, Estrov Z. Outcome of philadelphia chromosome-positive adult acute lymphoblastic. Leuk Lymphoma 2000; 36(3-4): 263-73.
[50]
Kukoc-Zivojnov N, Puccetti E, Chow KU, et al. Prostate apoptosis response gene-4 (par-4) abrogates the survival function of p185bcr-abl in hematopoietic cells. Exp Hematol 2004; 32(7): 649-56.
[51]
Boehrer S, Brieger A, Schaaf S, et al. In the erythroleukemic cell line hel prostate-apoptosis-response-gene-4 (par-4) fails to down-regulate bcl-2 and to promote apoptosis. Leuk Lymphoma 2004; 45(7): 1445-51.
[52]
Zhang L, Xu H-G, Lu C. A novel long non-coding rna t-all-r-lncr1 knockdown and par-4 cooperate to induce cellular apoptosis in t-cell acute lymphoblastic leukemia cells. Leuk Lymphoma 2014; 55(6): 1373-82.
[53]
Roussigne M, Cayrol C, Clouaire T, Amalric F, Girard J-P. THAP1 is a nuclear proapoptotic factor that links prostate-apoptosis-response-4 (par-4) to pml nuclear bodies. Oncogene 2003; 22(16): 2432-42.
[54]
Lu C, Li J-Y, Ge Z, et al. Par-4/THAP1 complex and notch3 competitively regulated pre-mrna splicing of ccar1 and affected inversely the survival of t-cell acute lymphoblastic leukemia cells. Oncogene 2013; 32(50): 5602-13.
[55]
Chow KU, Nowak D, Hofmann W, Schneider B, Hofmann W-K. Imatinib induces apoptosis in cll lymphocytes with high expression of par-4. Leukemia 2005; 19(6): 1103-5.
[56]
McKenna MK, Noothi SK, Alhakeem SS, et al. Novel role of prostate apoptosis response-4 tumor suppressor in b-cell chronic lymphocytic leukemia. Blood 2018; 131(26): 2943-54.
[57]
Ahmed MM, Sheldon D, Fruitwala MA, et al. Downregulation of par-4, a pro-apoptotic gene, in pancreatic tumors harboring k-ras mutation. Int J Cancer 2008; 122(1): 63-70.
[58]
Mann KM, Ying H, Juan J, Jenkins NA, Copeland G. KRAS-related proteins in pancreatic cancer. Pharmacol Ther 2016; 168: 29-42.
[59]
Azmi AS, Philip PA, Zafar SF, Sarkar FH. PAR-4 as a possible new target for pancreatic cancer therapy. Expert Opin Ther Targets 2010; 14(6): 611-20.
[60]
Azmi AS, Ahmad A, Banerjee S, et al. Chemoprevention of pancreatic cancer : Characterization of par-4 and its modulation by 3, 3 ′diindolylmethane (DIM). Pharm Res 2008; 25(9): 2117-24.
[61]
Azmi AS, Wang Z, Burikhanov R, et al. Critical role of prostate apoptosis response-4 in determining the sensitivity of pancreatic cancer cells to small-molecule inhibitor-induced apoptosis. Mol Cancer Ther 2008; 7(9): 2884-93.
[62]
Azmi AS, Aboukameel A, Bao B, et al. Selective Inhibitors of nuclear export block pancreatic cancer cell proliferation and reduce tumor growth in mice. Gastroenterol 2013; 144(2): 447-56.
[63]
Tan J, You Y, Xu T, et al. Par-4 downregulation confers cisplatin resistance in pancreatic cancer cells via pi3k/akt pathway-dependent emt. Toxicol Lett 2014; 224(1): 7-15.
[64]
DeSantis CE, Ma J, Goding Sauer A, Newman LA, Jemal A. Breast cancer statistics, 2017, racial disparity in mortality by state. CA Cancer J Clin 2017; 67: 439-48.
[65]
Zahir N, Weaver VM. Death in the third dimension: apoptosis regulation and tissue architecture. Curr Opin Genet Dev 2004; 14(1): 71-80.
[66]
Fung C, Lock R, Gao S, Salas E, Debnath J. Induction of Autophagy during extracellular matrix detachment promotes cell survival. Mol Biol Cell 2008; 19(1): 797-806.
[67]
de Bessa Garcia SA, Pereira MC, Nagai MA. Expression pattern of the pro-apoptotic gene par-4 during the morphogenesis of mcf-10a human mammary epithelial cells. Cancer Microenviron 2011; 4(1): 33-8.
[68]
Irby RB, Kline CL. Par-4 as a potential target for cancer therapy. Expert Opin Ther Targets 2013; 17(1): 77-87.
[69]
Zapata-Benavides P, Méndez-Vázquez JL, González-Rocha TR. at al. Expression of prostate apoptosis response (par-4) is associated with progesterone receptor in breast cancer. Arch Med Res 2009; 40(7): 595-9.
[70]
Alvarez JV, Pan T. chi Ruth J, et al. Par-4 Downregulation promotes breast cancer recurrence by preventing multinucleation following targeted therapy. Cancer Cell 2013; 24(1): 30-44.
[71]
Méndez-López LF, Zapata-Benavides P, Zavala-Pompa A, et al. Immunohistochemical analysis of prostate apoptosis response-4 (par-4) in mexican women with breast cancer: a preliminary study. Arch Med Res 2010; 41(4): 261-8.
[72]
Casolari DA, Pereira MC, De Bessa Garcia SA, Nagai MA. Insulin-like Growth Factor-1 and 17B-Estradiol down-Regulate Prostate apoptosis response-4 expression in mcf-7 breast cancer cells. Int J Mol Med 2011; 28(3): 337-42.
[73]
Pereira MC, De Bessa-Garcia SA, Burikhanov R, et al. Prostate apoptosis response-4 is involved in the apoptosis response to docetaxel in mcf-7 breast cancer cells. Int J Oncol 2013; 43(2): 531-8.
[74]
Cheema SK, Mishra SK, Rangnekar VM, et al. Par-4 Transcriptionally regulates bcl-2 through a wt1-binding site on the bcl-2 promoter. J Biol Chem 2003; 278(22): 19995-20005.
[75]
Shrestha-Bhattarai T, Hebbar N, Rangnekar VM. Par(-4) oxysm in breast cancer. Cancer Cell 2013; 24(1): 3-5.
[76]
Amin H, Nayak D, Ur Rasool R, et al. Par-4 dependent modulation of cellular β-catenin by medicinal plant natural product derivative 3-azido withaferin A. Mol Carcinog 2016; 55(5): 864-81.
[77]
Salis O, Bedir A, Ozdemir T, Okuyucu A, Alacam H. The relationship between anticancer effect of metformin and the transcriptional regulation of certain genes (CHOP, CAV-1, HO-1, SGK-1 and Par-4) on MCF-7 cell line. Eur J Pharm Sci 2014; 18: 1602-9.
[78]
Sarkar A, Chiocca EA. Glioblastoma and malignant astrocytoma. Am Brain Tumors Assoc 2016; pp. 384-407.
[80]
Louis DN, Perry A, Reifenberger G, et al. The 2016 world health organization classification of tumors of the central nervous system: a summary. Acta Neuropathol 2016; 131(6): 803-20.
[81]
Wang Q, Hu B, Hu X, et al. Tumor evolution of glioma-intrinsic gene expression subtypes associates with immunological changes in the microenvironment. Cancer Cell 2017; 32(1): 42-56.e6.
[82]
Yan H, Jones S, Riggins GJ, et al. IDH1 and IDH2 mutations in gliomas. New English J Med 2009; 360(8): 765-73.
[83]
Watanabe T, Nobusawa S, Kleihues P, Ohgaki H. IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas. Am J Pathol 2009; 174(4): 1149-53.
[84]
Reitman ZJ, Yan H. Isocitrate dehydrogenase 1 and 2 mutations in cancer: alterations at a crossroads of cellular metabolism. J Natl Cancer Inst 2010; 102(13): 932-41.
[85]
Liu Y, Glibert MR, Kyprianou N, Rangnekar VM, Horbinski C. The Tumor suppressor prostate apoptosis response-4 (par-4) is regulated by mutant idh1 and kills glioma stem cells. Acta Neuropathol 2014; 128(5): 723-32.
[86]
Zou J, Zhu L, Jiang X, et al. Curcumin Increases Breast Cancer Cell Sensitivity to Cisplatin by Decreasing FEN1 Expression. Oncotarget 2018; 9(13): 11268-78.
[87]
Kanai M. Therapeutic applications of curcumin for patients with pancreatic cancer. World J Gastroenterol 2014; 20(28): 9384-91.
[88]
Li Y, Zhang T. Targeting cancer stem cells by curcumin and clinical applications. Cancer Lett 2014; 346(2): 197-205.
[89]
Thayyullathil F, Rahman A, Pallichankandy S, Patel M, Galadari S. ROS-dependent prostate apoptosis response-4 (par-4) up-regulation and ceramide generation are the prime signaling events associated with curcumin-induced autophagic cell death in human malignant glioma. FEBS Open Bio 2014; 4: 763-76.
[90]
Jagtap JC, Dawood P, Shah RD, et al. Expression and regulation of prostate apoptosis response-4 (par-4) in human glioma stem cells in drug-induced apoptosis. PLoS One 2014; 9(2): e88505.
[91]
Jagtap JC, Parveen D, Shah RD, et al. Secretory prostate apoptosis response (par)-4 sensitizes multicellular spheroids (mcs) of glioblastoma multiforme cells to tamoxifen-induced cell death. FEBS Open Bio 2015; 5: 8-19.
[92]
Subburayan K, Thayyullathil F, Pallichankandy S, Rahman A, Galadari S. Par-4-Dependent p53 up-regulation plays a critical role in thymoquinone-induced cellular senescence in human malignant glioma cells. Cancer Lett 2018; 426: 80-97.
[93]
Fernández-Pello S, Hofmann F, Tahbaz R, et al. A systematic review and meta-analysis comparing the effectiveness and adverse effects of different systemic treatments for non-clear cell renal cell carcinoma. Eur Urol 2017; 71(3): 426-36.
[94]
Lee T-J, Jang J-H, Noh H-J, et al. Overexpression of par-4 sensitizes trail-induced apoptosis via inactivation of nf-kappab and akt signaling pathways in renal cancer cells. J Cell Biochem 2010; 109(5): 885-95.
[95]
Murali R, Soslow RA, Weigelt B. Classification of Endometrial carcinoma: more than two types. Lancet Oncol 2014; 15(7): e268-78.
[96]
Groothuis PG, Dassen HH, Romano A, Punyadeera C. Estrogen and the endometrium: lessons learned from gene expression profiling in rodents and human. Hum Reprod Update 2007; 13(4): 405-17.
[97]
Brasseur K, Fabi F, Adam P, et al. Post-translational regulation of the cleaved fragment of par-4 in ovarian and endometrial cancer cells. Oncotarget 2016; 7(24): 36971-87.
[98]
Saegusa M, Hashimura M, Kuwata T, Okayasu I. Transcriptional regulation of pro-apoptotic par-4 by nf-kb/p65 and its function in controlling cell kinetics during early events in endometrial tumourigenesis. J Pathol 2010; 221(1): 26-36.
[99]
Brasseur K, Gevry N, Asselin E. Chemoresistance and targeted therapies in ovarian and endometrial cancers. Oncotarget 2017; 8(3): 4008-42.
[100]
Chaudhry P, Singh M, Parent S, Asselin E. Prostate apoptosis response 4 (par-4), a novel substrate of caspase-3 during apoptosis activation. Mol Cell Biol 2012; 32(4): 826-39.
[101]
Katoch A, Suklabaidya S, Chakraborty S, Nayak D. Dual role of par-4 in abrogation of emt and switching on mesenchymal to epithelial transition (met) in metastatic pancreatic cancer cells. Mol Carcinog 2018; 57(9): 1102-15.
[102]
Gashaw I, Ellinghaus P, Sommer A, Asadullah K. What makes a good drug target? drug discov. Today 2011; 16: 1037-43.
[103]
Apoptosis C, Regression T, Chakraborty M, et al. Par-4 drives trafficking and activation of fas and fasl to induce prostate cancer. Cancer Res 2001; 61: 7255-63.
[104]
Zhao Y, Burikhanov R, Qiu S, et al. Cancer resistance in transgenic mice expressing the sac module of par-4. Cancer Res 2007; 67(19): 9276-85.
[105]
Zhao Y, Burikhanov R, Brandon J, et al. Systemic par-4 inhibits non-autochthonous tumor growth. Cancer Biol Ther 2011; 12(2): 152-7.
Article Metrics
56
4
1
1