Molecule Information

General Information of the Molecule (ID: Mol04370)

• Name: Caspase-3 (CASP3) ,Homo sapiens
• Synonyms: Apopain ; Cysteine protease CPP32 ; Protein Yama ; SREBP cleavage activity 1
• Molecule Type: Protein
• Gene Name: CASP3
• Gene ID: 836
• Sequence:
  MENTENSVDSKSIKNLEPKIIHGSESMDSGISLDNSYKMDYPEMGLCIIINNKNFHKSTG
  MTSRSGTDVDAANLRETFRNLKYEVRNKNDLTREEIVELMRDVSKEDHSKRSSFVCVLL
  S HGEEGIIFGTNGPVDLKKITNFFRGDRCRSLTGKPKLFIIQACRGTELDCGIETDSGV
  DD DMACHKIPVEADFLYAYSTAPGYYSWRNSKDGSWFIQSLCAMLKQYADKLEFMHILT
  RVN RKVATEFESFSFDATFHAKKQIPCIVSMLTKELYFYH
• Function: Thiol protease that acts as a major effector caspase involvedin the execution phase of apoptosis .Following cleavage and activation by initiator caspases , mediates execution of apoptosis by catalyzing cleavageof many proteins . At the onset of apoptosis, it proteolytically cleavespoly polymerase PARP1 at a '216-Asp-|-Gly-217' bond.Cleaves and activates sterol regulatory element binding proteins between the basic helix-loop-helix leucine zipper domain andthe membrane attachment domain . Cleaves and activatescaspase-6, -7 and -9 . Cleaves and inactivates interleukin-18 . Involved in the cleavage ofhuntingtin . Triggers cell adhesion in sympatheticneurons through RET cleavage . Cleaves and inhibitsserine/threonine-protein kinase AKT1 in response to oxidative stress. Acts as an inhibitor of type I interferon productionduring virus-induced apoptosis by mediating cleavage of antiviralproteins CGAS, IRF3 and MAVS, thereby preventing cytokineoverproduction . Also involved in pyroptosis bymediating cleavage and activation of gasdermin-E . Cleaves XRCC4 and phospholipidscramblase proteins XKR4, XKR8 and XKR9, leading to promotephosphatidylserine exposure on apoptotic cell surface . Cleaves BIRC6 following inhibition of BIRC6-caspasebinding by DIABLO/SMAC .{ECO:0000250|UniProtKB:Q60431, ECO:0000269|PubMed:10497198,ECO:0000269|PubMed:16374543, ECO:0000269|PubMed:18723680,ECO:0000269|PubMed:20566630, ECO:0000269|PubMed:21357690,ECO:0000269|PubMed:23152800, ECO:0000269|PubMed:23650375,ECO:0000269|PubMed:23845944, ECO:0000269|PubMed:30878284,ECO:0000269|PubMed:33725486, ECO:0000269|PubMed:35338844,ECO:0000269|PubMed:35446120, ECO:0000269|PubMed:36758104,ECO:0000269|PubMed:36758106, ECO:0000269|PubMed:37993714,ECO:0000269|PubMed:7596430, ECO:0000269|PubMed:7774019,ECO:0000269|PubMed:8696339, ECO:0000269|PubMed:9334240}.
• Uniprot ID: CASP3_HUMAN
• Ensembl ID: ENSG0000016430520
• HGNC ID: HGNC:1504

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

Investigative Drug(s) 1 drug(s) in total

Isoarnebin 4

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Oral squamous cell carcinoma [ICD-11: 2B6E.0] [2]

• Sensitive Disease: Oral squamous cell carcinoma [ICD-11: 2B6E.0]
• Sensitive Drug: Isoarnebin 4
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Apoptosis signaling pathway; Activation; hsa04210
• In Vitro Model: SCC9 cells; Tongue; Homo sapiens (Human); CVCL_1685
• In Vitro Model: H357 cells; Oral; Homo sapiens (Human); CVCL_2462
• In Vitro Model: HaCaT cells; Tongue; Homo sapiens (Human); CVCL_0038
• Experiment for Molecule Alteration: Reactive oxygen species measurement assay; Mitochondrial membrane potential measurement assay; CD spectroscopy assay; DNA interaction assay; qRT-PCR; Western blot assay
• Experiment for Drug Resistance: Drug release assay; Cell viability assay; Morphological assay; Clonogenic assay; Tumor spheres assay; Annexin V-FITC/PI staining assay; Antimigratory assay
• Mechanism Description: Our study revealed the release time and anticancer potential of Shk on the SCC9 and H357 oral cancer cell lines. We investigated the antiproliferative, antimigratory, cell cycle arresting and apoptosis promoting activity of Shk in oral cancer cells by performing MTT and morphological assay, colony, and tumor sphere formation assay, AO/EtBr and DAPI staining, Annexin V-FITC/PI staining, assay for reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) measurement, comet assay, qRT-PCR, and western blot analysis. We also checked the interaction of DNA and Shk by docking and CD spectroscopy and EtBr displacement assay. As a result, we found that Shk reduced the viability, proliferation, and tumorigenicity of SCC9 and H357 cells in a time and concentration-dependent manner. We obtained half-maximal inhibitory concentration (IC50) at 0.5 uM for SCC9 and 1.25 uM for H357. It promotes apoptosis via overexpressing proapoptotic Bax and caspase 3 via enhancing ROS that leads to MMP depletion and DNA damage and arrests cells at the G2/M & G2/S phase. The antimigratory activity of Shk was performed by analyzing the expression of markers of epithelial-mesenchymal transition like E-cadherin, ZO-1, N-cadherin, and vimentin. These overall results recommended that Shk shows potent anticancer activity against oral cancer cell lines in both in vitro and ex vivo conditions. So, it could be an excellent agent for the treatment of oral cancer.

References

• Ref 1: Ginsenoside Rg3 overcomes tamoxifen resistance through inhibiting glycolysis in breast cancer cells. Cell Biol Int. 2024 Apr;48(4):496-509.
• Ref 2: Shikonin Stimulates Mitochondria-Mediated Apoptosis by Enhancing Intracellular Reactive Oxygen Species Production and DNA Damage in Oral Cancer Cells. J Cell Biochem. 2025 Jan;126(1):e30671.