Blocks to thyroid cancer cell apoptosis can be overcome by inhibition of the MAPK and PI3K/AKT pathways

Abstract

Current treatment for recurrent and aggressive/anaplastic thyroid cancers is ineffective. Novel targeted therapies aimed at the inhibition of the mutated oncoprotein BRAFV600E have shown promise in vivo and in vitro but do not result in cellular apoptosis. TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis in a tumor-selective manner by activating the extrinsic apoptotic pathway. Here, we show that a TRAIL-R2 agonist antibody, lexatumumab, induces apoptosis effectively in some thyroid cancer cell lines (HTh-7, TPC-1 and BCPAP), while more aggressive anaplastic cell lines (8505c and SW1736) show resistance. Treatment of the most resistant cell line, 8505c, using lexatumumab in combination with the BRAFV600E inhibitor, PLX4720, and the PI3K inhibitor, LY294002, (triple-drug combination) sensitizes the cells by triggering both the extrinsic and intrinsic apoptotic pathways in vitro as well as 8505c orthotopic thyroid tumors in vivo. A decrease in anti-apoptotic proteins, pAkt, Bcl-xL, Mcl-1 and c-FLIP, coupled with an increase in the activator proteins, Bax and Bim, results in an increase in the Bax to Bcl-xL ratio that appears to be critical for sensitization and subsequent apoptosis of these resistant cells. Our results suggest that targeting the death receptor pathway in thyroid cancer can be a promising strategy for inducing apoptosis in thyroid cancer cells, although combination with other kinase inhibitors may be needed in some of the more aggressive tumors initially resistant to apoptosis.

Role of p38 MAPK activation and mitochondrial cytochrome-c release in allicin-induced apoptosis in SK-N-SH cells

“…The MAPK signaling pathway plays an important role in regulating apoptosis induced by various cellular stresses and chemotherapeutic agents [45]. However, the detailed mechanisms of these pathways in cell death remain elusive.…”

Combretastatin A4 Regulates Proliferation, Migration, Invasion, and Apoptosis of Thyroid Cancer Cells via PI3K/Akt Signaling Pathway

“…The PI3K/Akt signaling pathway is also responsible for modulating multiple processes in thyroid cancer cells [29]. For instance, down-regulation of PI3K and Akt phosphorylation inhibits thyroid cancer cell proliferation, invasion, and apoptosis [30,31]. Thus, we detected the PI3K/Akt signaling pathway proteins to reveal the molecular mechanisms of CA4-activated thyroid cancer cells.…”

Modeling Anaplastic Thyroid Carcinoma in the Mouse

“…In fact, 81.3% of ATC have been found to carry genetic alterations that could activate both pathways [32]. Recent studies have shown that blocking these two essential pathways in aggressive thyroid cancer cells allow for their sensitization to novel targeted therapies and traditional chemotherapeutic compounds [37, 20]. …”