Inhibition of JK184-Induced Cytoprotective Autophagy Potentiates JK184 Antitumor Effects in Breast Cancer

Breast cancer (BCa) is the most common aggressive tumor with limited curative therapeutic options available among women worldwide. JK184 is a potent Hedgehog inhibitor that regulates the glioma-dependent transcriptional activity. Although some studies have indicated that JK184 can kill BCa cells, it remains unclear whether there are any events that limit the use of JK184 in BCa therapy. Here, we report that JK184 intervention induces BCa cell death involving the dysregulation of autophagy in a dose- and time-dependent manner. The induction of autophagy compromises the antiproliferative effect of JK184. Mechanistically, JK184 induces autophagy via inhibiting the Akt/mTOR pathway in BCa cells. Taken together, our findings unravel a novel mechanism for JK184 treatment in BCa, suggesting that JK184 in combination with autophagy inhibitor may be a potential therapeutic strategy for the clinical treatment of BCa.