Combination therapy induces unfolded protein response and cytoskeletal rearrangement leading to mitochondrial apoptosis in prostate cancer. Issue 7 (31st March 2016)

• Record Type: Journal Article
• Authors: Kumar, Sandeep; Chaudhary, Ajay K.; Kumar, Rahul; O'Malley, Jordan; Dubrovska, Anna; Wang, Xinjiang; Yadav, Neelu; Goodrich, David W.; Chandra, Dhyan
• Is Part Of: Molecular oncology. Volume 10:Issue 7(2016:Aug.)
• Page Start: 949
• Page End: 965
• Publication Date: 2016-03-31
• Subjects: Prostate cancer -- Anticancer drugs -- Unfolded protein response -- Combination therapy -- Apoptosis -- Mitochondria; Cancer -- Molecular aspects -- Periodicals; 616.994005
• DOI: 10.1016/j.molonc.2016.03.007
• Languages: English
• ISSNs: 1574-7891

Abstract

Abstract : Development of therapeutic resistance is responsible for most prostate cancer (PCa) related mortality. Resistance has been attributed to an acquired or selected cancer stem cell phenotype. Here we report the histone deacetylase inhibitor apicidin (APC) or ER stressor thapsigargin (TG) potentiate paclitaxel (TXL)‐induced apoptosis in PCa cells and limit accumulation of cancer stem cells. TXL‐induced responses were modulated in the presence of TG with increased accumulation of cells at G1‐phase, rearrangement of the cytoskeleton, and changes in cytokine release. Cytoskeletal rearrangement was associated with modulation of the cytoplasmic and mitochondrial unfolded protein response leading to mitochondrial dysfunction and release of proapoptotic proteins from mitochondria. TXL in combination with APC or TG enhanced caspase activation. Importantly, TXL in combination with TG induced caspase activation and apoptosis in X‐ray resistant LNCaP cells. Increased release of transforming growth factor‐beta (TGF‐β) was observed while phosphorylated β‐catenin level was suppressed with TXL combination treatments. This was accompanied by a decrease in the CD44+CD133+ cancer stem cell‐like population, suggesting treatment affects cancer stem cell properties. Taken together, combination treatment with TXL and either APC or TG induces efficient apoptosis in both proliferating and cancer stem cells, suggesting this therapeutic combination may overcome drug resistance and recurrence in PCa. Highlights: Thapsigargin and apicidin attenuate taxol‐induced G2/M cell cycle arrest. Cytoskeletal rearrangements associate with interleukin‐8 and interferon‐γ release. Persistent unfolded protein response induces mitochondrial apoptosis. Thapsigargin and apicidin potentiate taxol‐induced cancer cell death. Combination therapy may overcome taxol resistance in prostate cancer.