Abstract
The underlying cause of treatment failure in many cancer patients is intrinsic and acquired resistance to chemotherapy. Recently, histone deacetylase (HDAC) inhibitors have developed into a promising cancer treatment. However, resistance mechanism induced by HDAC inhibitors remains largely unknown. Here we report that a HDAC inhibitor, JNJ-2648158 induced transcription of XIAP by activating AP-1 expression, which conferring resistance to chemotherapeutics. Our results showed that high expression of c-Fos caused by HDAC inhibitor promoted AP-1 formation during acquired resistance towards chemo-drugs, indicating an extremely poor clinical outcome in breast cancers and liver cancers. Our study reveals a novel regulatory mechanism towards chemo-drug resistance, and suggests that XIAP may serve as a potential therapeutic target in those chemo-resistant cancer cells.
Highlights
Developing drug-resistant tumors in patients is a major obstacle in both conventional chemotherapeutics and novel targeted therapeutics [1]
In order to completely suppress most histone deacetylase (HDAC) in the certain cells such as MCF7 and MCF7/ARD cells (Figure 1A), we applied a maximal concentration of 50 nM JNJ for the treatment and we found that the toxicity of 50 nM JNJ was mild in the cell (Figure 1B)
We revealed the underlying resistant mechanisms caused by JNJ in MCF7/ADR cells, and it is due to the activation of the c-Fos/AP-1/XIAP signaling pathway in MCF7/ ADR cells
Summary
Developing drug-resistant tumors in patients is a major obstacle in both conventional chemotherapeutics and novel targeted therapeutics [1]. The major mechanisms of drug-resistance in cancer cells are diversified and complicated processes, including activating of DNA repair, decreasing drug influx, confiscating of drugs within intracellular organelles, increasing drug efflux, disabling of apoptosis pathways, and triggering of immune response etc. Novel mechanism involved in drug resistant cancer cells has been largely focused on the high expression of ATPbinding cassette (ABC) transporter proteins. They showed that the overexpressed ABC transporters through efflux the anticancer drugs from the cytoplasm of tumor cells to reduce drugs accumulation in cells and cause the very low therapeutic result [6, 7]. JNJ may function as a promising adjunct treatment, and we examined its potential effects towards chemo-resistant cancer patients
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