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Fas Signaling in Thyroid Carcinomas Is Diverted from Apoptosis to Proliferation

Authors' Affiliations: ¹ Department of Medical Oncology, Dana-Farber Cancer Institute; ² Department of Medicine and ³ Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts; ⁴ Department of Pathology, University of Athens; and ⁵ Laboratory of Environmental Mutagenesis and Carcinogenesis, Institute of Biology, NCSR "Demokritos," GR-15310, Athens, Greece

Requests for reprints: Constantine S. Mitsiades, Department of Medical Oncology, Dana-Farber Cancer Institute, Room M555, Mayer Building, 44 Binney Street, Boston, MA 02115. Phone: 617-792-7240; Fax: 617-812-7701; E-mail: Constantine_Mitsiades{at}dfci.harvard.edu.

Purpose: The death receptor Fas is present in thyroid carcinomas, yet fails to trigger apoptosis. Interestingly, Fas has been reported to be actually overexpressed in papillary thyroid carcinomas, suggesting that it may confer a survival advantage.

Experimental Design: We investigated the expression and activation status of Fas pathway mediators in thyroid carcinoma cell lines and tumor specimens.

Results: All cell lines tested express Fas-associated death domain, procaspase-8, procaspase-9, and procaspase-3; resistance to Fas-mediated apoptosis could not be attributed to lack of any of these apoptosis mediators. Moreover, Fas death domain mutations were not found in our study. The proteasome inhibitors MG132 and PS-341 (bortezomib, Velcade), which lead to accumulation of the nuclear factor B (NF-B) inhibitor IB, did not sensitize SW579 cells to Fas-mediated apoptosis, suggesting that resistance to Fas-mediated apoptosis is not due to proteasome or NF-B activity. Cross-linking of Fas in vitro induced recruitment of Fas-associated death domain–like interleukin-1ß–converting enzyme inhibitory protein (FLIP) instead of procaspase-8. Inhibition of FLIP expression with a FLIP antisense oligonucleotide resulted in significant sensitization to Fas-mediated apoptosis. Fas cross-linking promoted BrdUrd incorporation; activated the mitogen-activated protein kinase/extracellular signal–regulated kinase kinase/extracellular signal–regulated kinase, NF-B, and activator protein-1 pathways in thyroid carcinoma cells in vitro; and protected cells from tumor necrosis factor–related apoptosis-inducing ligand–induced apoptosis. We also found that good prognosis papillary thyroid carcinoma specimens exhibited higher immunoreactivity for cleaved (activated) caspase-8 than poor prognosis tumors.

Conclusions: In thyroid carcinomas, the proteolytic cleavage and activation of caspase-8 depends on the balance between expression levels for procaspase-8 and FLIP and correlates with favorable clinical prognosis. Fas may actually stimulate proliferation and confer a survival advantage to thyroid cancer cells.

Commentaries

FLIPping the Balance between Apoptosis and Proliferation in Thyroid Cancer

Robin Mathew and Eileen White
Clin. Cancer Res. 2006 12: 3648-3651. [Full Text] [PDF]

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