Abstract
Axl expression is deregulated in several cancer types, predicts poor overall patient survival and is linked to resistance to drug therapy. Here, we evaluated a library of natural compounds for inhibitors of Axl and identified dihydroartemisinin, the active principle of the anti-malarial drug artemisinin, as an Axl-inhibitor in prostate cancer. Dihydroartemisinin blocks Axl expression leading to apoptosis, decrease in cell proliferation, migration, and tumor development of prostate cancer cells. Dihydroartemisinin treatment synergizes with docetaxel, a standard of care in metastatic prostate cancer increasing overall survival of mice with human xenografts. Dihydroartemisinin control of miR-34a and miR-7 expression leads to inhibition of Axl expression in a process at least partially dependent on regulation of chromatin via methylation of histone H3 lysine 27 residues by Jumonji, AT-rich interaction domain containing 2 (JARID2), and the enhancer of zeste homolog 2. Our discovery of a previously unidentified miR-34a/miR-7/JARID2 pathway controlling dihydroartemisinin effects on Axl expression and inhibition of cancer cell proliferation, migration, invasion, and tumor formation provides new molecular mechanistic insights into dihydroartemisinin anticancer effect on prostate cancer with potential therapeutic implications.
Highlights
Prostate cancer (PCa), is the most frequent solid cancer in aging males, and the third leading cause of cancer death in the US1
Our group recently demonstrated that Axl is a relevant therapeutic target for metastatic castration-resistant PCa5
We demonstrated that DHA inhibits Axl expression, leading to decreased proliferation, migration, and invasion, induction of apoptosis of PCa cells and inhibition of tumor development in vivo
Summary
Prostate cancer (PCa), is the most frequent solid cancer in aging males, and the third leading cause of cancer death in the US1. The metastatic disease is the most important cause of increasing morbidity and mortality of PCa. The development of the metastasis stage of the disease involves multiple events, including the progression to hormone-independent status, which leaves physicians with very few treatment options. One major prerequisite to develop more effective targeted therapies is the identification of the most relevant cellular targets and enhancing understanding of the key pathophysiological pathways driving PCa progression. In this context, our group recently demonstrated that Axl is a relevant therapeutic target for metastatic castration-resistant PCa (mCRPCa)[5]
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