title: Caspase-3 mediated feedback activation of apical caspases in doxorubicin and TNF-alpha induced apoptosis.
abstract: Aberrant apoptosis has been associated with the development and therapeutic resistance of cancer. Recent studies suggest that caspase deficiency/downregulation is frequently detected in different cancers. We have previously shown that caspase-3 reconstitution significantly sensitized MCF-7 cells to doxorubicin and etoposide. In contrast to the well established role of caspase-3 as an effector caspase, the focus of this study is to delineate caspase-3 induced feedback activation of the apical caspases-2, -8, -9 and -10A in doxorubicin and TNF-alpha induced apoptosis. Using cell-free systems we show that caspases-9 and 2 are the most sensitive, caspase-8 is less sensitive and caspase-10A is the least sensitive to caspase-3 mediated-cleavage. When apoptosis is induced by doxorubicin or TNF-alpha in an intact cell model, cleavage of caspases-8 and -9, but not caspase-2, was markedly enhanced by caspase-3. Caspase-3 mediated-feedback and activation of caspase-8 and -9 in MCF-7/C3 cells is further supported by an increase in the cleavage of caspase-8 and 9 substrates and cytochrome c release. These data indicate that, in addition to its function as an effector caspase, caspase-3 plays an important role in maximizing the activation of apical caspases and crosstalk between the two major apoptotic pathways. The significant impact of caspase-3 on both effector and apical caspases suggests that modulation of caspase-3 activity would be a useful approach to overcome drug resistance in clinical oncology.
authors.affiliation: Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Shihe
authors.initials: S
authors.lastname: Yang
authors.forename: Ann D
authors.initials: AD
authors.lastname: Thor
authors.forename: Susan
authors.initials: S
authors.lastname: Edgerton
authors.forename: XiaoHe
authors.initials: X
authors.lastname: Yang
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis; D053455:Caspase 10 / Q000378:metabolism; D053143:Caspase 2 / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D003546:Cysteine Endopeptidases / Q000378:metabolism; D003600:Cytosol / Q000201:enzymology; D004317:Doxorubicin / Q000494:pharmacology*; D006801:Humans; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D014409:Tumor Necrosis Factor-alpha; D004317:Doxorubicin; C490360:CASP2 protein, human; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053455:Caspase 10; D053143:Caspase 2; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D003546:Cysteine Endopeptidases; C506438:CASP10 protein, human