Molecule Information

General Information of the Molecule (ID: Mol00269)

• Name: Caspase-8 (CASP8) ,Homo sapiens
• Synonyms: CASP-8; Apoptotic cysteine protease; Apoptotic protease Mch-5; CAP4; FADD-homologous ICE/ced-3-like protease; FADD-like ICE; FLICE; ICE-like apoptotic protease 5; MORT1-associated ced-3 homolog; MACH; MCH5
• Molecule Type: Protein
• Gene Name: CASP8
• Gene ID: 841
• Location: chr2:201233443-201361836[+]
• Sequence:
  MDFSRNLYDIGEQLDSEDLASLKFLSLDYIPQRKQEPIKDALMLFQRLQEKRMLEESNLS
  FLKELLFRINRLDLLITYLNTRKEEMERELQTPGRAQISAYRVMLYQISEEVSRSELRSF
  KFLLQEEISKCKLDDDMNLLDIFIEMEKRVILGEGKLDILKRVCAQINKSLLKIINDYEE
  FSKERSSSLEGSPDEFSNGEELCGVMTISDSPREQDSESQTLDKVYQMKSKPRGYCLIIN
  NHNFAKAREKVPKLHSIRDRNGTHLDAGALTTTFEELHFEIKPHDDCTVEQIYEILKIYQ
  LMDHSNMDCFICCILSHGDKGIIYGTDGQEAPIYELTSQFTGLKCPSLAGKPKVFFIQAC
  QGDNYQKGIPVETDSEEQPYLEMDLSSPQTRYIPDEADFLLGMATVNNCVSYRNPAEGTW
  YIQSLCQSLRERCPRGDDILTILTEVNYEVSNKDDKKNMGKQMPQPTFTLRKKLVFPSD
• Function: Thiol protease that plays a key role in programmed cell death by acting as a molecular switch for apoptosis, necroptosis and pyroptosis, and is required to prevent tissue damage during embryonic development and adulthood. Initiator protease that induces extrinsic apoptosis by mediating cleavage and activation of effector caspases responsible for the TNFRSF6/FAS mediated and TNFRSF1A induced cell death. Cleaves and activates effector caspases CASP3, CASP4, CASP6, CASP7, CASP9 and CASP10. Binding to the adapter molecule FADD recruits it to either receptor TNFRSF6/FAS mediated or TNFRSF1A. The resulting aggregate called death-inducing signaling complex (DISC) performs CASP8 proteolytic activation. The active dimeric enzyme is then liberated from the DISC and free to activate downstream apoptotic proteases. Proteolytic fragments of the N-terminal propeptide (termed CAP3, CAP5 and CAP6) are likely retained in the DISC. In addition to extrinsic apoptosis, also acts as a negative regulator of necroptosis: acts by cleaving RIPK1 at 'Asp-324', which is crucial to inhibit RIPK1 kinase activity, limiting TNF-induced apoptosis, necroptosis and inflammatory response. Also able to initiate pyroptosis by mediating cleavage and activation of gasdermin-D (GSDMD): GSDMD cleavage promoting release of the N-terminal moiety (Gasdermin-D, N-terminal) that binds to membranes and forms pores, triggering pyroptosis. Initiates pyroptosis following inactivation of MAP3K7/TAK1. Also acts as a regulator of innate immunity by mediating cleavage and inactivation of N4BP1 downstream of TLR3 or TLR4, thereby promoting cytokine production. May participate in the Granzyme B (GZMB) cell death pathways. Cleaves PARP1.
• Uniprot ID: CASP8_HUMAN
• Ensembl ID: ENSG00000064012
• HGNC ID: HGNC:1509

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 3 drug(s) in total

Cisplatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Gastric cancer [1]

• Resistant Disease: Gastric cancer [ICD-11: 2B72.1]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Notch1 signaling pathway; Activation; hsa04330
• In Vitro Model: SGC7901 cells; Gastric; Homo sapiens (Human); CVCL_0520
• In Vitro Model: BGC823 cells; Gastric; Homo sapiens (Human); CVCL_3360
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Notch 1 promotes cisplatin-resistant gastric cancer formation by upregulating LncRNA Ak022798 expression. First, we found that Notch 1 was highly expressed in the cisplatin-resistant gastric cancer cell lines SGC7901/DDP and BGC823/DDP cells. Furthermore, we used siRNA to interfere with LncRNA Ak022798 expression, and found that the expression of MRP1 and P-glycoprotein decreased significantly in SGC7901/DDP and BGC823/DDP cells, and their apoptosis as well as the expressions of caspase 3 and caspase 8 obviously increased.

Doxorubicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast cancer [2]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Resistant Drug: Doxorubicin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Epithelial mesenchymal transition signaling pathway; Activation; hsa01521
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: MDA-MB-468 cells; Breast; Homo sapiens (Human); CVCL_0419
• Experiment for Molecule Alteration: Western blot analysis; TUNEL assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Long noncoding RNA LINP1 acts as an oncogene and promotes chemoresistance against 5-fluoroutacil and doxorubicin by inhibiting chemotherapeutics-induced apoptosis (apoptosis-related proteins such as caspase-8, caspase-9 and Bax proteins) in breast cancer.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Lung cancer [3]

• Sensitive Disease: Lung cancer [ICD-11: 2C25.5]
• Sensitive Drug: Doxorubicin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT/ERK signaling pathway; Inhibition; hsa04010
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• Experiment for Molecule Alteration: Western blot analysis; Luciferase reporter assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Suppression of miR-155 in this cell line considerably reversed doxorubicin resistance, and doxorubicin-induced apoptosis and cell cycle arrest were recovered. Furthermore, reverse transcription-polymerase chain reaction and western blot analysis revealed that miR-155 suppression downregulated the expression of multidrug resistance protein 1, multidrug resistance-associated protein 1, breast cancer resistance protein, glutathione S-transferase-Pi, Survivin and B-cell lymphoma 2, and upregulated the expression of caspase-3 and caspase-8. In addition, it was found that miR-155 suppression inhibited the activation of AkT and extracellular signal-regulated kinase. The transcriptional activity of nuclear factor-kB and activator protein-1 was also downregulated.

Fluorouracil

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast cancer [2]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Resistant Drug: Fluorouracil
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Epithelial mesenchymal transition signaling pathway; Activation; hsa01521
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: MDA-MB-231 cells; Breast; Homo sapiens (Human); CVCL_0062
• In Vitro Model: MDA-MB-468 cells; Breast; Homo sapiens (Human); CVCL_0419
• Experiment for Molecule Alteration: Western blot analysis; TUNEL assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Long noncoding RNA LINP1 acts as an oncogene and promotes chemoresistance against 5-fluoroutacil and doxorubicin by inhibiting chemotherapeutics-induced apoptosis (apoptosis-related proteins such as caspase-8, caspase-9 and Bax proteins) in breast cancer.

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

Gastric cancer [ICD-11: 2B72]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Gastric tissue
• The Specified Disease: Gastric cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 4.34E-01; Fold-change: 8.94E-01; Z-score: 1.03E+00
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 8.83E-05; Fold-change: 4.44E-01; Z-score: 1.03E+00

Lung cancer [ICD-11: 2C25]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Lung
• The Specified Disease: Lung cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.10E-01; Fold-change: -2.00E-01; Z-score: -2.58E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 3.16E-01; Fold-change: -2.36E-02; Z-score: -2.78E-02

Breast cancer [ICD-11: 2C60]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Breast tissue
• The Specified Disease: Breast cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.75E-11; Fold-change: 8.29E-02; Z-score: 2.16E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 9.49E-02; Fold-change: 1.64E-01; Z-score: 2.47E-01

References

• Ref 1: Notch 1 promotes cisplatin-resistant gastric cancer formation by upregulating lncRNA AK022798 expression. Anticancer Drugs. 2015 Jul;26(6):632-40. doi: 10.1097/CAD.0000000000000227.
• Ref 2: Long noncoding RNA LINP1 acts as an oncogene and promotes chemoresistance in breast cancer. Cancer Biol Ther. 2018 Feb 1;19(2):120-131. doi: 10.1080/15384047.2017.1394543. Epub 2018 Jan 2.
• Ref 3: Effect of miR-155 knockdown on the reversal of doxorubicin resistance in human lung cancer A549/dox cells. Oncol Lett. 2016 Feb;11(2):1161-1166. doi: 10.3892/ol.2015.3995. Epub 2015 Dec 3.