Dabrafenib stimulates autophagy in thyroid carcinoma cells via HMGB-1.

Abstract

Autophagy has been implicated in the pathophysiology of thyroid cancer and in determining the response of cancer cells to anticancer therapy. Dabrafenib, a BRAF inhibitor, has demonstrated efficacy and safety in several types of cancers. However, it is unknown whether Dabrafenib exerts a protective effect on autophagy in thyroid carcinoma cells. In the current study, our findings demonstrate that treatment with Dabrafenib reduced cell viability and promoted LDH release in SW579 thyroid carcinoma cells. Dabrafenib was then shown to promote autophagy by increasing the level of Beclin1 and the LC3-II/LC3-I ratio while reducing the level of p62. Additionally, exposure to Dabrafenib upregulated the expression of HMGB-1 at both mRNA and protein levels. Interestingly, silencing of HMGB-1 abrogated Dabrafenib-induced autophagy, suggesting that the effects of Dabrafenib are mediated by HMGB-1. Further study revealed that Dabrafenib activated the JAK1/STAT1 signaling pathway and that blockage of the JAK1/STAT1 signaling pathway with its inhibitor Pyridone 6 ameliorated Dabrafenib-induced HMGB-1 upregulation and autophagy, implicating the involvement of the JAK1/STAT1 signaling pathway in this process. Collectively, these findings demonstrate that Dabrafenib induces autophagy in thyroid carcinoma cells via the JAK1/STAT1/HMGB-1 axis. Notably, this effect occurs independently of BRAF V600E mutation status, suggesting a novel therapeutic mechanism.