Most importantly, TCTP seems to inhibit the etoposide induced cel

Most importantly, TCTP seems to inhibit the etoposide induced cell death at the site of apoptosome formation via association with Apaf 1. Though previous selleck inhibitor studies indi cated that abnormal function of Apaf 1 correlates with loss of sensitivity upon cytotoxic therapy and that up regulation of TCTP is also related Inhibitors,Modulators,Libraries to the pathogenesis of chemoresistance in cancer cells, the exact molecular mechanisms and interactions are unknown. One example of negative regulation of apoptosome formation is the finding that constitutive overexpression of HSP70 is re lated to the resistance to apoptosis exhibited by particular tumor cells. HSP70 in part modulates the Apaf 1 function through its direct association with the CARD of Apaf 1, thereby inhibiting the oligomerization of Apaf 1 and asso ciation of Apaf 1 with procaspase 9.

To clarify the interaction of TCTP with Apaf 1, studies are underway to Inhibitors,Modulators,Libraries test whether endogenous TCTP also binds to Apaf 1 in HeLa cells. Because we observed Apaf 1 binding and truncation of TCTP in a single cell line following TCTP overexpression, other types of etoposide resistant cancer cells need to be explored for verifying the Apaf 1 TCTP interaction. Perturbation of apoptosis by Apaf 1 TCTP complex possibly involves Inhibitors,Modulators,Libraries the direct mechanism that inhibits the apoptosome. In addition, indirect mechanisms Inhibitors,Modulators,Libraries involving the regulation of certain molecules in apoptotic pathway may consti tute the TCTP induced chemoresistance. As HeLa cells are reported to retain the p53 mediated pathway, inhibition of p53 by TCTP is a possible mechanism that contributes to the TCTP induced chemoresistance through the regulation of MDM2 or Bax.

To clarify this, our future work will include the study of TCTP Apaf 1 interaction using the p53 silenced cells. Though TCTP associates with CARD region of Apaf 1 to which caspase 9 binds, this interaction did not inhibit the caspase 9 binding to Apaf 1 but abolished the production of active caspases. Following etoposide Inhibitors,Modulators,Libraries treatment, procaspase 9 was cleaved to 35 and 37 kDa fragments but TCTP did not inhibit the production of p35. Initially, interaction of procaspase 9 with Apaf 1 induces auto cleavage at Asp 315 of procaspase 9 to produce the p35. Once caspase 3 is activated by p35 containing apopto some, it mediates another cleavage of caspase 9 at Asp 330, which produces p37 to amplify the apoptotic signal via positive feedback on the remaining procaspase promotion 9. Therefore, selective inhibition of TCTP on the cleavage of procaspase 9 into p37 in etoposide treated cells indicates that TCTP may not be involved in the initial auto catalysis but inhibits the amplification of caspase cascade as it interrupts the cleavage at Asp 330.

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