FADD adaptor in cancer

Abstract

FADD (Fas Associated protein with Death Domain) is a key adaptor molecule transmitting the death signal mediated by death receptors. In addition, this multiple functional protein is implicated in survival/proliferation and cell cycle progression. FADD functions are regulated via cellular sublocalization, protein phosphorylation, and inhibitory molecules. In the present review, we focus on the role of the FADD adaptor in cancer. Increasing evidence shows that defects in FADD protein expression are associated with tumor progression both in mice and humans. Better knowledge of the mechanisms leading to regulation of FADD functions will improve understanding of tumor growth and the immune escape mechanisms, and could open a new field for therapeutic interventions.

Figure 1

Human and mouse FADD protein. Amino acids (AA) corresponding to the human FADD protein are marked in black, whereas AA corresponding to the mouse FADD protein are marked in grey. The death domain (DD) and death effector domain (DED) are essential for interaction with death receptors and transmission of the apoptotic signal. Human nuclear export sequence (NES in red) and nuclear localization sequence (NLS in blue) determine localization of the protein in the cytoplasm and the nucleus, which are associated with cell death and survival functions of the FADD protein, respectively. Human Ser 194 and mouse Ser 191 phosphorylation site (in purple) have a crucial role in survival/proliferation and cell cycle progression.

Figure 2

Apoptosis mediated by death receptors requires the FADD adaptor molecule. (A) Engagement of a Fas ligand trimer on a trimer of Fas leads to FADD adaptor molecule recruitment through homotypic DD interactions. FADD next binds initiator pro-caspase through DED interactions. This Fas/FADD/pro-caspase complex forms the Fas death-inducing signaling complex (DISC) since initiator pro-caspase activates a caspase cascade resulting in apoptotic death of the cell. Alternatively, c-FLIPs can promote cell survival by interacting with FADD through their respective DED, thus hindering recruitment and activation of initiator pro-caspase. (B) Signaling mediated by TNF-R1 implicates formation of two sequential complexes [61]. The complex I (in blue) contains the TNF-R1, the adaptor TRADD, the receptor interacting kinase (RIP), and the TNF-receptor associated factor 2 (TRAF2). It assemblies rapidly following TNF-α stimulation and activates the NF-kB pathway which in turn induces expression of survival genes, including c-FLIP. Later on, complex I dissociates from the TNF-R1 and is internalized. FADD can then bind the liberated DD of TRADD and recruits initiator pro-caspase, forming complex II (in red) which is cytoplasmic. Activation of initiator pro-caspase 8/10 in complex II results in apoptosis of the cell. Red box: DD; hatched red box: DED.

Figure 3

Lack of FADD expression confers survival/growth advantages on tumor cells. Absence of FADD protein confers multiple death receptor-mediated apoptosis resistance and allows tumor cells to co-express death receptors and ligands without committing cell death. (A) Lack of FADD contributes to immune escape and resistance to chemotherapy. FADD deficient tumor cells resist death receptor-mediated apoptosis induced by TIL and chemotherapeutic drugs. Anthracyclines increase Fas and FasL expression on tumor cells. Etoposide induces Fas receptor trimerization, leading to Fas-mediated cell death independently of FasL expression. Both drugs enhance TRAIL-R2-mediated apoptosis. (B) Lack of FADD contributes to tumor counter-attack. Lack of FADD expression allows many types of tumor cells to express innocuously functional FasL that can kill TIL. Secretion of TNF-α by AML cells can have cytotoxic effects on TIL. (C) Lack of FADD contributes to tumor growth. In the absence of FADD, Fas signaling leads to a proliferative signal instead of an apoptotic one. Concomitant death receptor and ligand expression, in the absence of FADD, allows autocrine (in red) and paracrine (in orange) proliferation of tumor cells. Activated TIL can contribute to paracrine (in purple) proliferation of FADD-deficient tumor cells.