c-Myc Blazing a Trail of Death: Coupling of the Mitochondrial and Death Receptor Apoptosis Pathways by c-Myc

Abstract

TRAIL ligand induces selectively apoptosis in tumor cells by binding to two death receptors (DR4 and DR5) and holds promise as a potential therapeutic agent against cancer. While it has been known for long time that TRAIL receptors are commonly expressed in wide variety of normal tissues, it is not well understood why TRAIL kills tumor cells but leaves normal cells unharmed. The prototypic oncogene c-Myc promotes the cell cycle and simultaneously primes activation of the Bcl-2 family controlled mitochondria apoptosis pathway. A striking reflection of the c-Myc-dependent apoptotic sensitization is the dramatic c-Myc-induced vulnerability of cells to TRAIL and other death receptor ligands. Here we summarize the recent findings regarding the death mechanisms of TRAIL/TRAIL receptor system and the connection of c-Myc to the mitochondrial apoptosis pathway, focusing on our work that couples c-Myc via Bak to the TRAIL death receptor pathway. Finally, we present a mitochondria-priming model to explain how c-Myc-Bak interaction amplifies the TRAIL-induced caspase 8-Bid pathway to induce full-blown apoptosis. We discuss the implications of these findings for understanding the selective cytotoxicity of TRAIL and for the therapeutic exploitation of the death receptor pathway. DeAth receptors: Guilty of MurDer beyonD reAsonAble Doubt?TNF and TRAIL. Tumor necrosis factor-alpha (TNF) is a founding member of large TNF-family of proteins and was once considered in cancer research community as nothing less than phenomenal protein due to its ability to exert cytotoxic effects towards about one third of cancer cell lines without harming non-transformed cell lines. 1,2 However, the systemic administration of recombinant TNF caused severe side effects, including hemorrhagic necrosis, cachexia, fever and shock in laboratory animals and this precluded systemically administered TNF from clinical use. 3,4 The observed side effects were not caused by any rampant cell deaths triggered by the death ligand TNF, but rather they reflected effects of the cytokine TNF, which was found to play a key role in regulation of immunity and inflammation responses. 5 Indeed, inhibitors of TNF show promise in treatment of inflammation-linked disorders such as rheumatoid arthritis. 6 Discovery of TNF-related apoptosis-inducing ligand (TRAIL/Apo2L) and its two TNF receptor 1 related and death domain containing signaling receptors DR4 and DR5 brought death receptors back to attention of cancer field since TRAIL performed well where TNF had failed. TRAIL was demonstrated to exhibit TNF-like selective apoptotic activity towards tumor cells in vitro and in vivo and importantly, unlike TNF, TRAIL has been well tolerated in preclinical toxicity assays. 7,8 These findings quickly prompted several TRAIL based cancer therapies, which are currently in phase I and II clinical trials. 9 TRAIL receptors DR4 and DR5 are constitutively expressed in wide variety of tissues 10,11 (see also NCBI UniGene's EST ProfileViewer) and the ligated receptors can induce apopt...

The IKK2/NF-κB pathway suppresses MYC-induced lymphomagenesis

“…[44][45][46] BID, a BH3-only protein promoting cytochrome c release, had been connected to MYC-induced cell-death priming. 47 Most significantly, we detected strong up-regulation of Fas, a death receptor previously linked to MYC-induced apoptosis. MYC has been shown to sensitize cells to Fas-induced death.…”

Far upstream element-binding protein-1, a novel caspase substrate, acts as a cross-talker between apoptosis and the c-myc oncogene

“…However, this oncoprotein is also involved in the induction of apoptosis through a Bax-dependent mechanism and signal amplification through a process designated 'caspase feedback amplification loop' during apoptosis (Nieminen et al, 2007;Cao et al, 2008). These earlier reports suggest that c-Myc sensitizes cells to apoptosis by promoting the activation of the mitochondrial apoptosis pathway.…”

“…In particular, c-Myc induces apoptosis by triggering Bax oligomerization (Lalier et al, 2007;Cao et al, 2008). Furthermore, c-Myc acts as a gatekeeper of the caspase feedback amplification loop (Nieminen et al, 2007). Consequently, fine regulation of c-Myc may be important in determining the cell fate between apoptosis and growth.…”

Loss of Macroautophagy Promotes or Prevents Fibroblast Apoptosis Depending on the Death Stimulus

“…However, it is well recognized that death receptorinduced caspase 8 activation requires the actions of effector caspases. Caspase 8 activation sufficient to induce cell death does not occur until effector caspases are activated by the mitochondrial death pathway and act to promote further caspase 8 cleavage via the caspase feedback amplification loop (57)(58)(59). Consistent with the conclusion that in the absence of autophagy pro-apoptotic mitochondrial factors augmented caspase 8 activation in our model are data that increased caspase 8 activation did not occur until a late time point when caspase 3 and PARP cleavage had already resulted from activation of the mitochondrial death pathway.…”