Ochratoxin A affects COS cell adhesion and signaling.
Ochratoxin A (OTA), a metabolite produced by strains of Aspergillus and Penicillium, has nephritogenic, carcinogenic, and teratogenic activity in animals and humans. Nanomolar concentrations of OTA promote apoptosis in a cell-type specific fashion. In this study, we have analyzed the molecular mechanism by which OTA affects COS cell adhesion and signaling resulting in an apoptotic response. OTA, at noncytotoxic doses, was able to detach collagen- and fibronectin-adherent cells from immobilized substratum. However, prior to inducing detachment of adherent cells, OTA caused apoptosis as measured by caspase-3 activation. The treatment of adherent cells by OTA caused a reduction of tyrosine phosphorylation levels of FAK and of the adapter protein paxillin. The down-regulation of FAK preceded apoptosis and cell detachment induced by OTA. The mycotoxin was also able to cause a decrease of the phosphorylation levels of the two Shc isoforms, P66 and P52, in adherent cells. Since these Shc isoforms have been implicated in the activation of protein kinase c-Src, which is required for FAK tyrosine phosphorylation, the observed dephosphorylation of FAK and of the FAK substrate paxillin by OTA could be ascribed to the early down-regulation of Shc isoforms. However, whether FAK and Shc phosphorylation contribute both to the same pathway leading to the induction of apoptosis by OTA or are involved in two parallel signaling pathways remains to be investigated.
Dipartimento di Patologia e Sanità Animale, Università di Napoli Federico II, 80137 Napoli, Italy.
Antonio
A
Scibelli
Simona
S
Tafuri
Maria C
MC
Ferrante
Elena
E
Alimenti
Barbara
B
Naso
Antonia
A
Lucisano
Norma
N
Staiano
Rossella
R
Della Morte
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019556:COS Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3; D020169:Caspases / Q000096:biosynthesis; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D051416:Focal Adhesion Protein-Tyrosine Kinases; D009183:Mycotoxins / Q000494:pharmacology*; D009793:Ochratoxins / Q000494:pharmacology*; D051419:Paxillin; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism
D015815:Cell Adhesion Molecules; D003598:Cytoskeletal Proteins; D009183:Mycotoxins; D009793:Ochratoxins; D051419:Paxillin; D010750:Phosphoproteins; C025589:ochratoxin A; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D051416:Focal Adhesion Protein-Tyrosine Kinases; D053148:Caspase 3; D020169:Caspases