Dataset Information

Knockdown of cytokeratin 8 overcomes chemoresistance of chordoma cells by aggravating endoplasmic reticulum stress through PERK/eIF2? arm of unfolded protein response and blocking autophagy.

ABSTRACT: Chordoma is a malignant primary osseous spinal tumor with pronounced chemoresistance. However, the mechanisms of how chordoma cells develop chemoresistance are still not fully understood. Cytokeratin 8 (KRT8) is a molecular marker of notochordal cells, from which chordoma cells were believed to be originated. In this study, we showed that either doxorubicin or irinotecan promoted KRT8 expression in both CM319 and UCH1 cell lines, accompanied by an increased unfolded protein response and autophagy activity. Then, siRNA-mediated knockdown of KRT8 chemosensitized chordoma cells in vitro. Mechanistic studies showed that knockdown of KRT8 followed by chemotherapy aggravated endoplasmic reticulum stress through PERK/eIF2? arm of unfolded protein response and blocked late-stage autophagy. Moreover, suppression of the PERK/eIF2? arm of unfolded protein response using PERK inhibitor GSK2606414 partially rescued the apoptotic chordoma cells but did not reverse the blockage of the autophagy flux. Finally, tumor xenograft model further confirmed the chemosensitizing effects of siKRT8. This study represents the first systematic investigation into the role of KRT8 in chemoresistance of chordoma and our results highlight a possible strategy of targeting KRT8 to overcome chordoma chemoresistance.

SUBMITTER: Wang D

PROVIDER: S-EPMC6877560 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Knockdown of cytokeratin 8 overcomes chemoresistance of chordoma cells by aggravating endoplasmic reticulum stress through PERK/eIF2α arm of unfolded protein response and blocking autophagy.

Wang Di D Zhang Peiran P Xu Xiaolong X Wang Jianhui J Wang Dong D Peng Pandi P Zheng Chao C Meng Qing-Jun QJ Yang Liu L Luo Zhuojing Z

Cell death & disease 20191125 12

Chordoma is a malignant primary osseous spinal tumor with pronounced chemoresistance. However, the mechanisms of how chordoma cells develop chemoresistance are still not fully understood. Cytokeratin 8 (KRT8) is a molecular marker of notochordal cells, from which chordoma cells were believed to be originated. In this study, we showed that either doxorubicin or irinotecan promoted KRT8 expression in both CM319 and UCH1 cell lines, accompanied by an increased unfolded protein response and autophag ...[more]

PMID: 31767864

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Project description:Prostate cancer chemoresistance is a major therapeutic problem, and the underlying mechanism is not well understood and effective therapies to overcome this problem are not available. Phosphodiesterase-4 (PDE4), a main intracellular enzyme for cAMP hydrolysis, has been previously shown to involve in the early chemo-sensitive prostate cancer cell proliferation and progression, but its role in the more-advanced chemo-resistant prostate cancer is completely unknown. Here we found that the expression of PDE4 subtype, PDE4D, is highly elevated in the chemo-resistant prostate cancer cells (DU145-TxR and PC3-TxR) in comparison to the chemo-sensitive prostate cancer cells (DU145 and PC3). Inhibition of PDE4D with a potent and selective PDED4 inhibitor, Eggmanone, effectively decreases the invasion and proliferation as well as induces cell death of the chemo-resistant prostate cancer cells (DU145-TxR and PC3-TxR). These results were confirmed by siRNA knockdown of PDE4D. We and colleagues previously reported that Eggmanone can effectively blocked sonic Hedgehog signaling via PDE4D inhibition, and here our study suggests that that Eggmanone downregulated proliferation of the chemo-resistant prostate cancer cells via sonic Hedgehog signaling. In addition, Eggmanone treatment dose-dependently increases docetaxel cytotoxicity to DU145-TxR and PC3-TxR. As cancer stem cells (CSCs) are known to be implicated in cancer chemoresistance, we further examined Eggmanone impacts on CSC-like properties in the chemo-resistant prostate cancer cells. Our study shows that Eggmanone effectively down-regulates the expression of CSCs' marker genes Nanog and ABC sub-family G member 2 (ABCG2) and attenuates sphere formation in DU145-TxR and PC3-TxR cells. In summary, our work shows that Eggmanone effectively overcomes the chemoresistance of prostate cancer cells presumably through sonic Hedgehog signaling and targeting CSCs, suggesting that Eggmanone may serve as a novel agent for chemo-resistant prostate cancer.

Dataset Information

Knockdown of cytokeratin 8 overcomes chemoresistance of chordoma cells by aggravating endoplasmic reticulum stress through PERK/eIF2? arm of unfolded protein response and blocking autophagy.

Publications

Knockdown of cytokeratin 8 overcomes chemoresistance of chordoma cells by aggravating endoplasmic reticulum stress through PERK/eIF2α arm of unfolded protein response and blocking autophagy.

Similar Datasets

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