IAPs cause resistance to TRAIL-dependent apoptosis in follicular thyroid cancer.

IAPs cause resistance to TRAIL-dependent apoptosis in follicular thyroid cancer.

Endocr Relat Cancer. 2018 Jan 09;:

Authors: Werner TA, Nolten I, Dizdar L, Riemer J, Schütte SC, Verde PE, Raba K, Schott M, Knoefel WT, Krieg A

Abstract
Follicular thyroid cancer's (FTC) excellent long-term prognosis is mainly dependent on complete surgical removal and postoperative radioactive iodine (RAI) treatment. However, once the tumour becomes RAI refractory the 10-year disease specific survival rate drops below 10 %. The aim of our study was to evaluate the prognostic and biological role of the TRAIL system in FTC and to elucidate the influence of small molecule mediated antagonization of inhibitor of apoptosis proteins (IAPs) on TRAIL-sensitivity in vitro. Tissue microarrays were constructed from forty-four patients with histologically confirmed FTC. Expression levels of TRAIL and its receptors were correlated with clinicopathological data, overall as well as recurrence-free survival. Non-iodine retaining FTC cell lines TT2609-C02 and FTC133 were treated with recombinant human TRAIL alone and in combination with Smac mimetics GDC-0152 or Birinapant. TRAIL-R2/DR5 as well as TRAIL-R3/DcR1 and TRAIL-R4/DcR2 were significantly higher expressed in advanced tumour stages. Both decoy receptors were negatively associated with recurrence free and overall survival. TRAIL-R4/DcR2 additionally proved to be an independent negative prognostic marker in FTC (HR = 1.446, 95 % CI: 1.144 - 1.826; p < 0.001). In vitro, the co-incubation of Birinapant or GDC-0152 with rh-TRAIL sensitised FTC cell lines for TRAIL induced apoptosis, through degradation of cIAP1/2. The TRAIL system plays an important role in FTC tumour biology. Its decoy receptors are associated with poor prognosis and earlier recurrence. The degradation of cIAP1/2 sensitises FTC cells to TRAIL induced apoptosis and might highlight a new point of attack in patients with RAI refractory disease.

PMID: 29317481 [PubMed - as supplied by publisher]

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