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Molecule Details

General Information of the Molecule
Name
X-linked inhibitor of apoptosis protein (XIAP)
Synonyms
hILP; hIAP3; hIAP-3; Xlinked IAP; X-linked IAP; RING-type E3 ubiquitin transferase XIAP; Inhibitor of apoptosis protein 3; ILP; IAPlike protein; IAP3; IAP-like protein; IAP-3; E3 ubiquitinprotein ligase XIAP; E3 ubiquitin-protein ligase XIAP; Baculoviral IAP repeatcontaining protein 4; Baculoviral IAP repeat-containing protein 4; BIRC4; API3
Gene Name
XIAP
Gene ID
331
Sequence
MTFNSFEGSKTCVPADINKEEEFVEEFNRLKTFANFPSGSPVSASTLARAGFLYTGEGDT
VRCFSCHAAVDRWQYGDSAVGRHRKVSPNCRFINGFYLENSATQSTNSGIQNGQYKVENY
LGSRDHFALDRPSETHADYLLRTGQVVDISDTIYPRNPAMYSEEARLKSFQNWPDYAHLT
PRELASAGLYYTGIGDQVQCFCCGGKLKNWEPCDRAWSEHRRHFPNCFFVLGRNLNIRSE
SDAVSSDRNFPNSTNLPRNPSMADYEARIFTFGTWIYSVNKEQLARAGFYALGEGDKVKC
FHCGGGLTDWKPSEDPWEQHAKWYPGCKYLLEQKGQEYINNIHLTHSLEECLVRTTEKTP
SLTRRIDDTIFQNPMVQEAIRMGFSFKDIKKIMEEKIQISGSNYKSLEVLVADLVNAQKD
SMQDESSQTSLQKEISTEEQLRRLQEEKLCKICMDRNIAIVFVPCGHLVTCKQCAEAVDK
CPMCYTVITFKQKIFMS
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Function
Multi-functional protein which regulates not only caspases and apoptosis, but also modulates inflammatory signaling and immunity, copper homeostasis, mitogenic kinase signaling, cell proliferation, as well as cell invasion and metastasis. Acts as a direct caspase inhibitor. Directly bind to the active site pocket of CASP3 and CASP7 and obstructs substrate entry. Inactivates CASP9 by keeping it in a monomeric, inactive state. Acts as an E3 ubiquitin-protein ligase regulating NF-kappa-B signaling and the target proteins for its E3 ubiquitin-protein ligase activity include: RIPK1, CASP3, CASP7, CASP8, CASP9, MAP3K2/MEKK2, DIABLO/SMAC, AIFM1, CCS and BIRC5/survivin. Ubiquitinion of CCS leads to enhancement of its chaperone activity toward its physiologic target, SOD1, rather than proteasomal degradation. Ubiquitinion of MAP3K2/MEKK2 and AIFM1 does not lead to proteasomal degradation. Plays a role in copper homeostasis by ubiquitinationg COMMD1 and promoting its proteasomal degradation. Can also function as E3 ubiquitin-protein ligase of the NEDD8 conjugation pathway, targeting effector caspases for neddylation and inactivation. Regulates the BMP signaling pathway and the SMAD and MAP3K7/TAK1 dependent pathways leading to NF-kappa-B and JNK activation. Acts as an important regulator of innate immune signaling via regulation of Nodlike receptors (NLRs). Protects cells from spontaneous formation of the ripoptosome, a large multi-protein complex that has the capability to kill cancer cells in a caspase-dependent and caspase-independent manner. Suppresses ripoptosome formation by ubiquitinating RIPK1 and CASP8. Acts as a positive regulator of Wnt signaling and ubiquitinates TLE1, TLE2, TLE3, TLE4 and AES. Ubiquitination of TLE3 results in inhibition of its interaction with TCF7L2/TCF4 thereby allowing efficient recruitment and binding of the transcriptional coactivator beta-catenin to TCF7L2/TCF4 that is required to initiate a Wnt-specific transcriptional program.
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Uniprot ID
XIAP_HUMAN
EC Number
EC: 2.3.2.27
Pfam
PF00653
KEGG ID
hsa331
TTD ID
T16769
A List of Drug Combination(s) Able to Regulate This Molecule
          Expression Regulation     Click to Show/Hide the Drug Combination Regulating This Molecule
                 Down-regulation     Click to Show/Hide
                    Drug Combination 1 Down-regulating the Expression of This Molecule [1]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Pterostilbene   NP Info  + TNF-related apoptosis inducing ligand    Drug Info 
                    Structure +
                    Drug Combination 2 Down-regulating the Expression of This Molecule [2]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Shikonin   NP Info  + TNF-related apoptosis inducing ligand    Drug Info 
                    Structure +
                    Drug Combination 3 Down-regulating the Expression of This Molecule [3]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name 6-shogaol   NP Info  + Gemcitabine   Drug Info 
                    Structure +
                    Drug Combination 4 Down-regulating the Expression of This Molecule [4]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Gambogic acid   NP Info  + Doxorubicin   Drug Info 
                    Structure +
                    Drug Combination 5 Down-regulating the Expression of This Molecule [5]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Gambogic acid   NP Info  + Cisplatin   Drug Info 
                    Structure +
                    Drug Combination 6 Down-regulating the Expression of This Molecule [6]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Ursolic acid   NP Info  + Gemcitabine   Drug Info 
                    Structure +
                    Drug Combination 7 Down-regulating the Expression of This Molecule [7]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Ursolic acid   NP Info  + Oxaliplatin   Drug Info 
                    Structure +
                    Drug Combination 8 Down-regulating the Expression of This Molecule [8]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Epigallocatechin gallate   NP Info  + TNF-related apoptosis inducing ligand    Drug Info 
                    Structure +
                    Drug Combination 9 Down-regulating the Expression of This Molecule [9]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Cardamonin   NP Info  + Cisplatin   Drug Info 
                    Structure +
                    Drug Combination 10 Down-regulating the Expression of This Molecule [10]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Kaempferol   NP Info  + TNF-related apoptosis inducing ligand    Drug Info 
                    Structure +
                    Drug Combination 11 Down-regulating the Expression of This Molecule [11]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Thymoquinone   NP Info  + Gemcitabine   Drug Info 
                    Structure +
                    Drug Combination 12 Down-regulating the Expression of This Molecule [12]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Gallic acid   NP Info  + Cisplatin   Drug Info 
                    Structure +
                    Drug Combination 13 Down-regulating the Expression of This Molecule [13]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Matrine   NP Info  + Cisplatin   Drug Info 
                    Structure +
                    Drug Combination 14 Down-regulating the Expression of This Molecule [14]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Elemene   NP Info  + Cisplatin   Drug Info 
                    Structure +
                    Drug Combination 15 Down-regulating the Expression of This Molecule [15]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Rottlerin   NP Info  + TNF-related apoptosis inducing ligand    Drug Info 
                    Structure +
                    Drug Combination 16 Down-regulating the Expression of This Molecule [16]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Triptolide   NP Info  + TNF-related apoptosis inducing ligand    Drug Info 
                    Structure +
                    Drug Combination 17 Down-regulating the Expression of This Molecule [17]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Arsenic trioxide   NP Info  + Cisplatin   Drug Info 
                    Structure +
                    Drug Combination 18 Down-regulating the Expression of This Molecule [18]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Shikonin   NP Info  + Gemcitabine   Drug Info 
                    Structure +
                    Drug Combination 19 Down-regulating the Expression of This Molecule [19]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Curcumin   NP Info  + TNF-related apoptosis inducing ligand    Drug Info 
                    Structure +
                    Drug Combination 20 Down-regulating the Expression of This Molecule [20]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Bufalin   NP Info  + 5-fluorouracil   Drug Info 
                    Structure +
                    Drug Combination 21 Down-regulating the Expression of This Molecule [21]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Bufalin   NP Info  + TNF-related apoptosis inducing ligand    Drug Info 
                    Structure +
                    Drug Combination 22 Down-regulating the Expression of This Molecule [22]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Silibinin   NP Info  + Vorinostat   Drug Info 
                    Structure +
                    Drug Combination 23 Down-regulating the Expression of This Molecule [23]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Rhein   NP Info  + Calphostin c   Drug Info 
                    Structure +
                    Drug Combination 24 Down-regulating the Expression of This Molecule [24]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Flavopiridol   NP Info  + Carfilzomib   Drug Info 
                    Structure +
                    Drug Combination 25 Down-regulating the Expression of This Molecule [25]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Gambogic acid   NP Info  + Imatinib   Drug Info 
                    Structure +
                    Drug Combination 26 Down-regulating the Expression of This Molecule [26]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Sulforaphane   NP Info  + Cisplatin   Drug Info 
                    Structure +
                    Drug Combination 27 Down-regulating the Expression of This Molecule [27]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Emodin   NP Info  + Gemcitabine   Drug Info 
                    Structure +
                    Drug Combination 28 Down-regulating the Expression of This Molecule [28]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Triptolide   NP Info  + BIIB021   Drug Info 
                    Structure +
                    Drug Combination 29 Down-regulating the Expression of This Molecule [29]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Arsenic trioxide   NP Info  + 2-deoxy-D-glucose   Drug Info 
                    Structure +
                    Drug Combination 30 Down-regulating the Expression of This Molecule [30]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Arsenic trioxide   NP Info  + Lonidamine   Drug Info 
                    Structure +
                    Drug Combination 31 Down-regulating the Expression of This Molecule [31]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Luteolin   NP Info  + CD55-TRAIL   Drug Info 
                    Structure +
                    Drug Combination 32 Down-regulating the Expression of This Molecule [32]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Triptolide   NP Info  + Temozolomide   Drug Info 
                    Structure +
                    Drug Combination 33 Down-regulating the Expression of This Molecule [33]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Gingerol   NP Info  + TNF-related apoptosis inducing ligand    Drug Info 
                    Structure +
                    Drug Combination 34 Down-regulating the Expression of This Molecule [34]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Luteolin   NP Info  + TNF-related apoptosis inducing ligand    Drug Info 
                    Structure +
                    Drug Combination 35 Down-regulating the Expression of This Molecule [22]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Silibinin   NP Info  + Trichostatin A   Drug Info 
                    Structure +
                    Drug Combination 36 Down-regulating the Expression of This Molecule [35]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Amentoflavone   NP Info  + Sorafenib   Drug Info 
                    Structure +
                 Up-regulation     Click to Show/Hide
                    Drug Combination 1 Up-regulating the Expression of This Molecule [36]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Flavopiridol   NP Info  + Irinotecan   Drug Info 
                    Structure +
                    Drug Combination 2 Up-regulating the Expression of This Molecule [37]
                    Detail(s)  Combination Info  click to show the detail info of this combination
                    Name Gambogic acid   NP Info  + TNF-related apoptosis inducing ligand    Drug Info 
                    Structure +
Natural Product(s) of This Target
1 Diallyl disulfide  NP Info  Investigative Allium sativum
Drug(s) of This Target
1 Birinapant  Drug Info  Phase 2 Lymphoma
References
Reference 1 Pterostilbene Enhances TRAIL-Induced Apoptosis through the Induction of Death Receptors and Downregulation of Cell Survival Proteins in TRAIL-Resistance Triple Negative Breast Cancer Cells. J Agric Food Chem. 2017 Dec 27;65(51):11179-11191.
Reference 2 Shikonin sensitizes A549 cells to TRAIL-induced apoptosis through the JNK, STAT3 and AKT pathways. BMC Cell Biol. 2018 Dec 29;19(1):29.
Reference 3 Antitumor activity of gemcitabine can be potentiated in pancreatic cancer through modulation of TLR4/NF-kappaB signaling by 6-shogaol. AAPS J. 2014 Mar;16(2):246-57.
Reference 4 Suppression of NF-KappaB signaling and P-glycoprotein function by gambogic acid synergistically potentiates adriamycin -induced apoptosis in lung cancer. Curr Cancer Drug Targets. 2014;14(1):91-103.
Reference 5 Combination of gambogic acid with cisplatin enhances the antitumor effects on cisplatin-resistant lung cancer cells by downregulating MRP2 and LRP expression. Onco Targets Ther. 2016 Jun 2;9:3359-68.
Reference 6 Ursolic acid inhibits the growth of human pancreatic cancer and enhances the antitumor potential of gemcitabine in an orthotopic mouse model through suppression of the inflammatory microenvironment. Oncotarget. 2016 Mar 15;7(11):13182-96.
Reference 7 Ursolic acid synergistically enhances the therapeutic effects of oxaliplatin in colorectal cancer. Protein Cell. 2016 Aug;7(8):571-85.
Reference 8 Green tea polyphenol EGCG sensitizes human prostate carcinoma LNCaP cells to TRAIL-mediated apoptosis and synergistically inhibits biomarkers associated with angiogenesis and metastasis. Oncogene. 2008 Mar 27;27(14):2055-63.
Reference 9 Cardamonin enhances the anti-proliferative effect of cisplatin on ovarian cancer. Oncol Lett. 2018 Mar;15(3):3991-3997.
Reference 10 The flavonoid kaempferol sensitizes human glioma cells to TRAIL-mediated apoptosis by proteasomal degradation of survivin. Mol Cancer Ther. 2008 Nov;7(11):3566-74.
Reference 11 Thymoquinone Pretreatment Overcomes the Insensitivity and Potentiates the Antitumor Effect of Gemcitabine Through Abrogation of Notch1, PI3K/Akt/mTOR Regulated Signaling Pathways in Pancreatic Cancer. Dig Dis Sci. 2015 Apr;60(4):1067-80.
Reference 12 Gallic acid has anticancer activity and enhances the anticancer effects of cisplatin in non?small cell lung cancer A549 cells via the JAK/STAT3 signaling pathway. Oncol Rep. 2019 Mar;41(3):1779-1788.
Reference 13 Effects of matrine in combination with cisplatin on liver cancer. Oncol Lett. 2021 Jan;21(1):66.
Reference 14 beta-Elemene, a novel plant-derived antineoplastic agent, increases cisplatin chemosensitivity of lung tumor cells by triggering apoptosis. Oncol Rep. 2009 Jul;22(1):161-70.
Reference 15 Rottlerin sensitizes glioma cells to TRAIL-induced apoptosis by inhibition of Cdc2 and the subsequent downregulation of survivin and XIAP. Oncogene. 2005 Jan 27;24(5):838-49.
Reference 16 Triptolide sensitizes pancreatic cancer cells to TRAIL-induced activation of the death receptor pathway. Cancer Lett. 2014 Jun 28;348(1-2):156-66.
Reference 17 Co-application of arsenic trioxide (As2O3) and cisplatin (CDDP) on human SY-5Y neuroblastoma cells has differential effects on the intracellular calcium concentration ([Ca2+]i) and cytotoxicity. Neurotoxicology. 2009 Mar;30(2):194-202.
Reference 18 Shikonin suppresses tumor growth and synergizes with gemcitabine in a pancreatic cancer xenograft model: Involvement of NF-kappaB signaling pathway. Biochem Pharmacol. 2014 Apr 1;88(3):322-33.
Reference 19 Curcumin sensitizes tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through reactive oxygen species-mediated upregulation of death receptor 5 (DR5). Carcinogenesis. 2005 Nov;26(11):1905-13.
Reference 20 Bufalin and 5-fluorouracil synergistically induce apoptosis in colorectal cancer cells. Oncol Lett. 2018 May;15(5):8019-8026.
Reference 21 Down-regulation of Cbl-b by bufalin results in up-regulation of DR4/DR5 and sensitization of TRAIL-induced apoptosis in breast cancer cells. J Cancer Res Clin Oncol. 2012 Aug;138(8):1279-89.
Reference 22 Epigenetic modifications and p21-cyclin B1 nexus in anticancer effect of histone deacetylase inhibitors in combination with silibinin on non-small cell lung cancer cells. Epigenetics. 2012 Oct;7(10):1161-72.
Reference 23 Rottlerin sensitizes colon carcinoma cells to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis via uncoupling of the mitochondria independent of protein kinase C. Cancer Res. 2003 Aug 15;63(16):5118-25.
Reference 24 Synergistic combination of flavopiridol and carfilzomib targets commonly dysregulated pathways in adrenocortical carcinoma and has biomarkers of response. Oncotarget. 2018 Aug 31;9(68):33030-33042.
Reference 25 Gambogic acid induces apoptosis in imatinib-resistant chronic myeloid leukemia cells via inducing proteasome inhibition and caspase-dependent Bcr-Abl downregulation. Clin Cancer Res. 2014 Jan 1;20(1):151-63.
Reference 26 Sulforaphane enhances the cisplatin sensitivity through regulating DNA repair and accumulation of intracellular cisplatin in ovarian cancer cells. Exp Cell Res. 2020 Aug 15;393(2):112061.
Reference 27 Enhanced antitumor efficacy by the combination of emodin and gemcitabine against human pancreatic cancer cells via downregulation of the expression of XIAP in vitro and in vivo. Int J Oncol. 2011 Nov;39(5):1123-31.
Reference 28 Synergistic cytotoxicity of BIIB021 with triptolide through suppression of PI3K/Akt/mTOR and NF-KappaB signal pathways in thyroid carcinoma cells. Biomed Pharmacother. 2016 Oct;83:22-32.
Reference 29 2-Deoxy-D-glucose cooperates with arsenic trioxide to induce apoptosis in leukemia cells: involvement of IGF-1R-regulated Akt/mTOR, MEK/ERK and LKB-1/AMPK signaling pathways. Biochem Pharmacol. 2012 Dec 15;84(12):1604-16.
Reference 30 Increased apoptotic efficacy of lonidamine plus arsenic trioxide combination in human leukemia cells. Reactive oxygen species generation and defensive protein kinase (MEK/ERK, Akt/mTOR) modulation. Biochem Pharmacol. 2011 Dec 1;82(11):1619-29.
Reference 31 Combination of oncolytic adenovirus and luteolin exerts synergistic antitumor effects in colorectal cancer cells and a mouse model. Mol Med Rep. 2017 Dec;16(6):9375-9382.
Reference 32 Triptolide synergistically enhances temozolomide-induced apoptosis and potentiates inhibition of NF-KappaB signaling in glioma initiating cells. Am J Chin Med. 2014;42(2):485-503.
Reference 33 Inhibition of the autophagy flux by gingerol enhances TRAIL-induced tumor cell death. Oncol Rep. 2015 May;33(5):2331-6.
Reference 34 The combination of TRAIL and luteolin enhances apoptosis in human cervical cancer HeLa cells. Biochem Biophys Res Commun. 2005 Aug 5;333(3):833-8.
Reference 35 Amentoflavone enhances sorafenib-induced apoptosis through extrinsic and intrinsic pathways in sorafenib-resistant hepatocellular carcinoma SK-Hep1 cells in vitro. Oncol Lett. 2017 Sep;14(3):3229-3234.
Reference 36 Augmentation of apoptosis and tumor regression by flavopiridol in the presence of CPT-11 in Hct116 colon cancer monolayers and xenografts. Clin Cancer Res. 2001 Dec;7(12):4209-19.
Reference 37 Gambogic acid sensitizes breast cancer cells to TRAIL-induced apoptosis by promoting the crosstalk of extrinsic and intrinsic apoptotic signalings. Food Chem Toxicol. 2018 Sep;119:334-341.
Reference 38 Inhibition of cell growth and induction of apoptosis via inactivation of NF-kappaB by a sulfurcompound isolated from garlic in human colon cancer cells. J Pharmacol Sci. 2007 Aug;104(4):374-83.
Reference 39 cIAPs and XIAP regulate myelopoiesis through cytokine production in an RIPK1- and RIPK3-dependent manner. Blood. 2014 Apr 17;123(16):2562-72.
Cite NPCDR
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Correspondence

X. N. Sun, Y. T. Zhang, Y. Zhou, X. C. Lian, L. L. Yan, T. Pan, T. Jin, H. Xie, Z. M. Liang, W. Q. Qiu, J. X. Wang, Z. R. Li, F. Zhu*, X. B. Sui*. NPCDR: natural product-based drug combination and its disease-specific molecular regulation. Nucleic Acids Research. 50(D1): 1324-1333 (2020). PMID: 34664659

Prof. Feng ZHU  (zhufeng@zju.edu.cn)

College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China


Prof. Xinbing SUI  (hzzju@hznu.edu.cn)

School of Pharmacy and Department of Medical Oncology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, China