FUTURE STRATEGIES IN THE TREATMENT OF AGGRESSIVE THYROID CANCER

Radioiodine-refractory and anaplastic thyroid cancers have a poor prognosis that may not be significantly altered by the current treatment regimens. Therefore there is a compelling need to identify potential new therapies. TNF-related apoptosis inducing ligand (TRAIL) induces apoptosis selectively in tumor cells, the IG20/MADD (Insulinoma-Glucagonoma), a novel human gene, is over-expressed in cancer and confers TRAIL resistance. Therefore, we aimed to investigate the effects of IG20/MADD knockdown on TRAIL induced-apoptosis in different types of thyroid cancer. Material and Methods. A shRNA expressing lentivirus was used to selectively knockdown IG20/MADD in the human papillary thyroid cancer (PTC) cell lines: TPC1, KTC1 and BCPAP, the human follicular thyroid cancer (FTC) cell lines: WRO and FTC133 and the human anaplastic thyroid cancer (ATC): C643, CAL62 and HTh7. Apoptosis was assessed by propidium iodide or TMRM staining or detection of activated caspase-3 by flow-cytometry. Results. TPC1, BCPAP, WRO, C643, CAL62 and HTh7 cells were sensitive to TRAIL-induced apoptosis, while KTC1, FTC133, FRO and 8505C cells were resistant to even high dose of TRAIL (100 ng/ml). Upon knockdown of IG20/MADD all the sensitive cell lines cells had increased susceptibility to TRAIL-induced apoptosis and previously resistant 8505C and FTC133 cells became sensitive to TRAIL. Only FRO cells could not be rescued from TRAIL resistance because of caspase 8 deficiency, which is not a common finding in in vivo thyroid tumors. Moreover, the combination of TRAIL with select Akt/mTOR (perifosine and everolimus) and/or MEK inhibitors (PD-0325901) showed an antagonistic effect on TRAIL-induced apoptosis in ATC C643 cells, but had no effect on ATC 8505C cells. Conclusions. IG20/MADD knockdown in TRAIL treated thyroid cancer cells enhanced apoptosis in sensitive cells and induced significant cytotoxicity in resistant cells. This effect was not enhanced significantly in the presence of various inhibitors of the MAPK/PI3K/Akt signaling pathways. TRAIL treatment combined with IG20/MADD knockdown may be a potential therapeutic modality for radioiodine-refractory and anaplastic thyroid cancer.