Targeted ovarian cancer treatment: the TRAILs of resistance

Abstract

Ovarian cancer (OC) is the leading cause of death from gynecological malignancies. Although most patients respond to the initial therapy when presenting with advanced disease, only 10-15% maintain a complete response following first-line therapy. Recurrence defines incurable disease in most cases. Despite improvements with conventional chemotherapy combinations, the overall cure rate remained mostly stable over the years. Increased long-term survival in OC patients will only be achieved through a comprehensive understanding of the basic mechanisms of tumor cell resistance. Such knowledge will translate into the development of new targeted strategies. In addition, because OC is considered to be a heterogeneous group of diseases with distinct gene expression profiles, it is likely that different approaches to treatment for distinct sub-types will be required to optimize response. One of the new promising anti-cancer therapies is the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). TRAIL has the ability to selectively induce apoptosis in tumor cells with little toxicity to normal cells. Death receptor ligands such as TRAIL rely on the activation of the apoptotic signaling pathway to destroy tumor cells. TRAIL induces the formation of a pro-apoptotic death-inducing signaling complex (DISC) via its death receptors, TRAIL receptor 1 (TRAIL R1) and TRAIL receptor 2 (TRAIL R2). The formation of the DISC activates caspase-8 which requires further signal amplification through the mitochondrial pathway for an efficient activation of effector caspases in OC cells. The initial enthusiasm for TRAIL has been hampered by accumulating data demonstrating TRAIL resistance in various tumor types including OC cells. There is, therefore, a need to identify markers of TRAIL resistance, which could represent new hits for targeted therapy that will enhance TRAIL efficacy. In addition, the identification of patients that are more likely to respond to TRAIL therapy would be highly desirable. In this review, we discuss the different molecular and cellular mechanisms leading to TRAIL resistance in OC. In particular, we address the mechanisms involved in intrinsic, acquired and environment-mediated TRAIL resistance, and their potential implication in the clinical outcome.

Keywords: Ovarian cancer; TRAIL; death receptors; resistance.

Figure 1

Apoptotic TRAIL signaling. Binding of TRAIL to death receptors (TRAIL R1, TRAIL R2) leads to the recruitment of the adaptor molecule, FADD. Pro-caspase-8 binds to FADD leading to DISC formation and resulting in its activation. Activated caspase-8 directly activates executioner caspases (caspase-3, -6, and -7) (type I cells) or cleaves Bid (type II cells). Translocation of the truncated Bid (tBid) to the mitochondria promotes the assembly of Bax-Bak oligomers and mitochondria outer membrane permeability changes. Cytochrome c is released into cytosol resulting in apoptosome assembly. Active caspase-9 then propagates a proteolytic cascade of effector caspases activation that leads to morphological hallmarks of apoptosis. Further cleavage of pro-caspase-8 by effector caspases generates a mitochondrial amplification loop that further enhances apoptosis. When FLIP levels are elevated in cells, caspase-8 preferentially recruits FLIP to form a caspase-8-FLIP heterodimer which does not trigger apoptosis.

Figure 2

Non-apoptotic TRAIL signaling. In cells that resistant to TRAIL-induced apoptosis, TRADD, TRAF2 and RIP1 bind to the receptor. This complex signals through NF-κB, p38 and JNK pathway resulting in the up-regulation of target genes involved in anti-apoptotic function and proliferation.

Figure 3

Model for ovarian cancer ascites-mediated protection from TRAIL-induced apoptosis. TRAIL binding to death receptors TRAIL-R1 and TRAIL-R2 results in death- inducing-signaling complex (DISC) formation, activation of procas-pase-8, Bid cleavage, release of cytochrome c from mitochondria, and caspase-9 and caspase-3 activation. Binding of ascites survival factors to avβ5 integrin leads to the phosphorylation of FAK and Akt. Akt activation up-regulates the levels of c-FLIP protein leading to inhibition of caspase-8. Ascites also activate the ERK pathway leading to up-regulation of the anti-apoptotic Mcl-1 protein.