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Cisplatin-enriching cancer stem cells confer multidrug resistance in non-small cell lung cancer via enhancing TRIB1/HDAC activity.

ABSTRACT: Chemotherapeutic agents are generally used as a frontline therapy for non-small cell lung cancer (NSCLC). However, resistance to chemotherapy arises rapidly in NSCLC, and the reasons for chemotherapy resistance have not been fully determined. Here, we found cisplatin, but not paclitaxel and doxorubicin, induced the enrichment of cancer stem cell (CSC) and conferred multidrug resistance in NSCLC cell lines. In vivo study confirmed drug-resistant tumors displayed the enhanced expressions of CSC transcription factors. Mechanistically, cisplatin treatment resulted in C/EBP-?-dependent increasing of TRIB1. The crucial role of TRIB1 in cisplatin-induced enrichment of CSC and drug resistance was verified by knockdown TRIB1. Interestingly, cisplatin treatment also contributed to the increasement of HDAC, the interaction of TRIB1 with HDAC, and inactivation of p53. Similarly, the silencing of HDAC led to reduction of cisplatin-induced CSC, and combined knockdown of HDAC and TRIB1 exhibited enhanced effect. Additionally, the combination of HDAC inhibitor and cisplatin showed a reinforced antitumor action in NSCLC cell lines with TRIB1-dependent manner and remarkably shrink tumors in xenograft models. Moreover, cisplatin-treated NSCLC patients with high levels of TRIB1 exhibited a significantly poorer prognosis. Our findings illustrate a novel perspective in the evolution of chemotherapy resistance and provide a promising approach for the treatment of patients with NSCLC.

SUBMITTER: Wang L

PROVIDER: S-EPMC5477570 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Cisplatin-enriching cancer stem cells confer multidrug resistance in non-small cell lung cancer via enhancing TRIB1/HDAC activity.

Wang Lihui L Liu Xing X Ren Yong Y Zhang Jingyuan J Chen Junli J Zhou Wenlong W Guo Wei W Wang Xiaoxuan X Chen Huiping H Li Meng M Yuan Xiangzhong X Zhang Xun X Yang Jingyu J Wu Chunfu C

Cell death & disease 20170413 4

Chemotherapeutic agents are generally used as a frontline therapy for non-small cell lung cancer (NSCLC). However, resistance to chemotherapy arises rapidly in NSCLC, and the reasons for chemotherapy resistance have not been fully determined. Here, we found cisplatin, but not paclitaxel and doxorubicin, induced the enrichment of cancer stem cell (CSC) and conferred multidrug resistance in NSCLC cell lines. In vivo study confirmed drug-resistant tumors displayed the enhanced expressions of CSC tr ...[more]

PMID: 28406482

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Project description:BACKGROUND:Cisplatin is a first-line drug for the treatment of human non-small cell lung cancer (NSCLC); however, the majority of patients will develop drug resistance after treatment. In order to overcome cisplatin resistance, it is important to understand the mechanisms underlying the resistance. METHODS:A gene microarray was used to screen for genes related to cisplatin resistance in NSCLC cell lines. Subsequently, the correlation between the HDAC, RXR and HtrA1 genes, in NSCLC, were verified using gene manipulation. Immunohistochemical staining was used to detect HDAC, RXR and HtrA1 expression in NSCLC specimens. Proliferation, migration and invasion assays were performed in vitro and in vivo to determine the role of the HDAC/RXR/HtrA1 signaling axis in cisplatin resistance, and luciferase reporter analysis and ChIP assays were performed to ascertain the mechanisms by which HDAC and RXR regulate the expression of HtrA1. Furthermore, in vitro and in vivo experiments were conducted in NSCLC cisplatin-resistant NSCLC to elucidate the effect of the low molecular weight compound, DW22, which targets the NSCLC cisplatin resistance HDAC/RXR/HtrA1 signaling pathway. RESULTS:HtrA1 was identified as a cisplatin resistance-related gene in NSCLC cells. The regulation of HtrA1 by HDAC and RXR significantly decreased the efficacy of cisplatin in NSCLC cells resistant to cisplatin. Immunohistochemistry results showed a negative relationship between HDAC1 and HtrA1, and a positive relationship between RXR? and HtrA1 in NSCLC patients' tissues. Notably, the expression of HDAC1 and HtrA1 can be considered as biomarkers for the efficacy of platinum-based drugs and prognosis in NSCLC patients. Mechanistically, the heterodimers of the nuclear receptor RXR, in combination with the enzyme, HDAC, regulate the transcription of HtrA1 in NSCLC cells. The rescue of HtrA1 expression by dual targeting of HDAC and RXR with the compound, DW22, significantly inhibited the proliferation, migration and invasion of NSCLC cells resistant to cisplatin, and induced NSCLC cell apoptosis. CONCLUSION:Our results indicate that HtrA1, a cisplatin resistance-related gene, is synergistically regulated by HDAC and RXR in NSCLC. Targeting the HDAC/RXR/HtrA1 signaling axis can rescue HtrA1 expression and reverse cisplatin resistance in NSCLC.

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Cisplatin-enriching cancer stem cells confer multidrug resistance in non-small cell lung cancer via enhancing TRIB1/HDAC activity.

Publications

Cisplatin-enriching cancer stem cells confer multidrug resistance in non-small cell lung cancer via enhancing TRIB1/HDAC activity.

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