Abstract
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.
Highlights
Breast cancer is the most diagnosed cancer in women, accounting for about 15% of all new cases [1]. e morbidity and mortality of BCa are expected to rise significantly in the decades
The immunofluorescence analysis results of colocalized LC3B and LAMP2 in BCa cells demonstrated that the colocalization of autophagosome and lysosome was more obvious after being treated with JK184 (Figure S4). us, these findings reveal that JK184 triggers complete autophagy flux in BCa cells
To further explore whether the Akt/mTOR pathway was involved in JK184-induced autophagy, we examined the levels of Akt/mTOR pathway-related proteins, including total or phosphorylated Akt, mTOR, p70S6K, and 4EBP1
Summary
Breast cancer is the most diagnosed cancer in women, accounting for about 15% of all new cases [1]. e morbidity and mortality of BCa are expected to rise significantly in the decades. The strategy of surgical resection combined with radiotherapy has afforded effective treatment outcomes for early or local disease [2]. Due to drug resistance or cancer recurrence, the current therapeutic strategies for BCa display compromised treatment outcome, and the overall prognosis for BCa patients remains poor. Erefore, there is an urgent need to develop novel chemotherapeutic drugs for the treatment of BCa patients [3]. Treatment of BCa cells with doxorubicin could trigger autophagy to inhibit doxorubicin-mediated apoptosis and restore growth inhibition [9]. Autophagy may play a role in mediating programmed cell death. Autophagy is an actionable target for improving therapy efficacy in BCa following identification of the biological roles of autophagy in treatment
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