Lysosome destabilization as a therapeutic approach to apoptosis-resistant thyroid carcinoma
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Poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC) are very aggressive and lethal neoplasms for which there is currently no effective treatment. Understanding mechanisms of intrinsic or acquired drug resistance in these tumors is critical for the design of effective therapeutic approaches. The rarity of these tumors and their rapid progression have proven to be major obstacles in the study of PDTC and ATC. By activating Kras and deleting p53 in the mouse thyroid we have generated a mouse of model of PDTC variably progressing to ATC. Cancer cells derived from these tumors are intrinsically resistant to cell death even when driver oncogenic signaling pathways are inhibited. Our studies suggest that this resistance is partly due to high expression levels of anti-apoptotic genes of the BCL2 family of proteins. Overexpression of these genes was also observed in a large subset of human thyroid carcinomas through dataset analysis.;Our ex vivo and in vivo studies using Obatoclax, a pan inhibitor of the antiapoptotic proteins of the BCL2 family have demonstrated that this drug is capable of inducing cell death in aggressive murine thyroid carcinoma cells. Obatoclax is a drug designed to induce apoptosis; however, our studies propose that this inhibitor does not induce cell death through apoptosis but rather through necrosis. This molecule localizes to the lysosomes of the cell where it blocks their normal function. Our findings suggest that Obatoclax induces alkalinization of the lysosomal lumen and subsequently the permeabilization of the lysosomal membrane. Moreover, the low pH of the organelle is crucial in the induction of cell death by Obatoclax, as prior neutralization of the lysosomes by treatment with V-ATPase inhibitors protects cells from the toxic effects of the drug.;Obatoclax induced variable drug sensitivity responses in human thyroid carcinoma cell lines. Furthermore a difference in sensitivity is also observed between transformed and non-transformed cells. Previous studies have reported that higher lysosomal activity in cancer cells is associated with enhanced tumorigenesis; but most importantly, this increased activity is also responsible for alterations in the structure of the organelle, which render cells sensitive to lysosomal membrane destabilization. Our findings suggest that Obatoclax induces necrosis through lysosomal destabilization and that aggressive, apoptosis-resistant cancer cells can be targeted through this mechanism. Even though further studies are needed to fully characterize the death mechanism elicited by Obatoclax, the results presented in this manuscript propose the use of lysosomal destabilizing agents as a potential therapeutic strategy in the treatment of thyroid cancer.
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