Fas-associated protein with death domain (FADD)， a pivotal adaptor protein transmitting apoptotic signals， is indispensable for the induction of extrinsic apoptosis. However， overexpression of FADD can form large， filamentous aggregates， termed death effector filaments (DEFs) by self-association and initiate apoptosis independent of receptor cross-linking. A mutant of FADD， which is truncated of the C-terminal tail (m-FADD， 182-205 aa) named N-FADD (m-FADD， 1-181 aa)， can dramatically up-regulate the strength of FADD self-association and increase apoptosis. In this study， it was found that over-expression of FADD or N-FADD caused apoptosis of B16F10 cells in vitro， even more， N-FADD ... More
Fas-associated protein with death domain (FADD)， a pivotal adaptor protein transmitting apoptotic signals， is indispensable for the induction of extrinsic apoptosis. However， overexpression of FADD can form large， filamentous aggregates， termed death effector filaments (DEFs) by self-association and initiate apoptosis independent of receptor cross-linking. A mutant of FADD， which is truncated of the C-terminal tail (m-FADD， 182-205 aa) named N-FADD (m-FADD， 1-181 aa)， can dramatically up-regulate the strength of FADD self-association and increase apoptosis. In this study， it was found that over-expression of FADD or N-FADD caused apoptosis of B16F10 cells in vitro， even more， N-FADD showed a more potent apoptotic effect than FADD. Meanwhile， Attenuated Salmonella Typhimurium strain VNP20009 was engineered to express FADD or N-FADD under the control of a hypoxia-induced NirB promoter and each named VNP-pN-FADD and VNP-pN-N-FADD. The results showed both VNP-pN-FADD and VNP-pN-N-FADD delayed tumor growth in B16F10 mice model， while VNP-pN-N-FADD suppressed melanoma growth more significantly than VNP-pN-FADD. Additionally， VNP-pN-FADD and VNP-pN-N-FADD induced apoptosis of tumor cells by activating caspase-dependent apoptotic pathway. Our results show that N-FADD is a more potent apoptotic inducer and VNP20009-mediated targeted expression of N-FADD provides a possible cancer gene therapeutic approach for the treatment of melanoma.
