Role of Focal Adhesion Kinase in Regulating YB–1–Mediated Paclitaxel Resistance in Ovarian Cancer

Kang, Yu; Hu, Wei; Ivan, Cristina; Dalton, Heather J.; Miyake, Takahito; Pecot, Chad V.; Zand, Behrouz; Liu, Tao; Huang, Jie; Jennings, Nicholas B.; Rupaimoole, Rajesha; Taylor, Morgan; Pradeep, Sunila; Wu, Sherry Y.; Lü, Chunhua; Wen, Yunfei; Huang, Jianfei; Liu, Jinsong; Sood, Anil K.

doi:10.1093/jnci/djt210

Cited by 160 publications

(146 citation statements)

References 40 publications

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“…More importantly, it was reported that a potential clinical niche for FAK tyrosine kinase inhibitor (TKi) may be used in patients with PCa to overcome chemoresistance because cotreatment with FAK TKi and docetaxel resulted in an additive attenuation of FAK and Akt phosphorylation and overcame the chemoresistant phenotype in PCa PC3 and DU-145 cells (35). Interestingly, FAK inhibition with vs-6063 overcame YB-1-mediated PTX resistance by an AKT-dependent pathway (36) in ovarian cancer. Additionally, the acquisition of drug resistance in ovarian cancer cells induced an extensive reorganization of the actin cytoskeleton, which governed the cellular mechanical properties, motility, and possibly intracellular drug transportation (37).…”

Section: Discussionmentioning

confidence: 99%

Exosome-derived microRNAs contribute to prostate cancer chemoresistance

Yang

Guan

et al. 2016

International Journal of Oncology

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Abstract. Certain microRNAs (miRNAs) play a key role in cancer cell chemoresistance. However, the pleiotropic functions of exosome-derived miRNAs on developing chemoresistance remain unknown. In the present study, we aimed to construct potential networks of miRNAs, which derived from the exosome of chemoresistant prostate cancer (PCa) cells, with their known target genes using miRNA expression profiling and bioinformatic tools. Global miRNA expression profiles were measured by microarray. Twelve miRNAs were initially selected and validated by qRT-PCR. Known targets of deregulated miRNAs were utilized using DIANA-TarBase database v6.0. The incorporation of deregulated miRNAs and target genes into KEGG pathways were utilized using DIANA-mirPath software. To construct potential miRNA regulatory networks, the overlapping parts of miRNAs and their targer genes from the selected KEGG pathway 'PCa progression (hsa05215)' were visualized by Cytoscape software. We identified 29 deregulated miRNAs, including 19 upregulated and 10 downregulated, in exosome samples derived from two kinds of paclitaxel resistance PCa cells (PC3-TXR and DU145-TXR) compared with their parental cells (PC3 and DU145). The enrichment results of deregulated miRNAs and known target genes showed that a few pathways were correlated with several critical cell signaling pathways. We found that hub hsa-miR3176, -141-3p, -5004-5p, -16-5p, -3915, -488-3p, -23c, -3673 and -3654 were potential targets to hub gene androgen receptor (AR) and phosphatase and tensin homolog (PTEN). Hub gene T-cell factors/lymphoid enhancer-binding factors 4 (TCF4) target genes were mainly regulated by hub hsa-miR-32-5, -141-3p, -606, -381 and -429. These results may provide a linkage between PCa chemoresistance and exosome regulatory networks and thus lead us to propose that AR, PTEN and TCF4 genes may be the important genes which are regulated by exosome miRNAs in chemoresistance cancer cells.

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Section: Discussionmentioning

confidence: 99%

Exosome-derived microRNAs contribute to prostate cancer chemoresistance

Yang

Guan

et al. 2016

International Journal of Oncology

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“…In addition to the pathways in cancer and pathways related to specified cancers (such as prostate and colorectal cancer), 4 pathways including ErbB signaling, focal adhesion, apoptosis and p53 signaling were enriched, suggesting that HNF1B may contribute to drug resistance in ovarian cancer via those pathways. ErbB signaling (91), focal adhesion (92,93), apoptosis (94,95) and p53 signaling (96,97) have been reported to associate with drug resistance in ovarian cancer. For example, miR-21 regulates drug resistance via apoptosis and cellular survival pathways (94), and loss of DOK2 induces carboplatin resistance in ovarian cancer via suppression of apoptosis (98).…”

Section: Discussionmentioning

confidence: 99%

Downregulation of HNF1 homeobox B is associated with drug resistance in ovarian cancer

Zhang²,

Gao

et al. 2014

Oncology Reports

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Abstract. The expression of HNF1 homeobox B (HNF1B) is associated with cancer risk in several tumors, including ovarian cancer, and its decreased expression play roles in cancer development. However, the study of HNF1B and cancer is limited, and its association with drug resistance in cancer has never been reported. On the basis of array data retrieved from Oncomine and Gene Expression Omnibus (GEO) online database, we found that the mRNA expression of HNF1B in 586 ovarian serous cystadenocarcinomas and in platinum-resistant A2780 epithelial ovarian cancer cells was significantly decreased, indicating a potential role of HNF1B in drug resistance in ovarian cancer. Based on this finding, comprehensive bioinformatics analyses, including protein/ gene interaction, protein-small molecule/chemical interaction, biological process annotation, gene co-occurrence and pathway enrichment analysis and microRNA-mRNA interaction, were performed to illustrate the association of HNF1B with drug resistance in ovarian cancer. We found that among the proteins/ genes, small molecules/chemicals and microRNAs which directly interacted with HNF1B, the majority was associated with drug resistance in cancer, particularly in ovarian cancer. Biological process annotation revealed that HNF1B closely related to 24 biological processes which were all notably associated with ovarian cancer and drug resistance. These results indicated that the downregulation of HNF1B may contribute to drug resistance in ovarian cancer, via its direct interactions with these drug resistance-related proteins/genes, small molecules/chemicals and microRNAs, and via its regulations on the drug resistance-related biological processes. Pathway enrichment analysis of 36 genes which co-occurred with HNF1B, ovarian cancer and drug resistance indicated that the HNF1B may perform its drug resistance-related functions through 4 pathways including ErbB signaling, focal adhesion, apoptosis and p53 signaling. Collectively, in this study, we illustrated for the first time that HNF1B may contribute to drug resistance in ovarian cancer, potentially through the 4 pathways. The present study may pave the way for further investigation of the drug resistance-related functions of HNF1B in ovarian cancer.

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“…Several studies also identified cofactors contributing to FAK overexpression (33)(34)(35)(36). FAK overexpression has been associated with breast cancer lung metastasis (37,38), and FAK inhibitors have been introduced in novel therapeutic strategies (20,(39)(40)(41). An association between FAK overexpression and lymphatic metastasis has been identified in non-small-cell lung, oral squamous cell, esophageal, gastric, tongue, laryngeal and endometrial cancer by retrospective analysis of clinical samples (42)(43)(44)(45)(46)(47)(48)(49).…”

Section: Discussionmentioning

confidence: 99%

“…The IC 50 was determined as described previously (20). Briefly, 3,000 cells were seeded in each well of a 96-well plate and allowed to adhere overnight.…”

Section: Spect-ct Imaging In Vivomentioning

confidence: 99%

Identification of lymphatic metastasis-associated genes in a metastatic ovarian cancer cell line

Kang

Cai³

et al. 2015

Molecular Medicine Reports

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Abstract. Ovarian cancer (OC) is the gynecological malignancy with the highest rate of mortality, and lymphatic metastasis is a critical factor in disease recurrence and prognosis. In the current study, the SKOV-3/LN403 cell line, which has high potential for lymph node metastasis was established as a result of four rounds of selection from retroperitoneal lymph nodes following intraperitoneal injections of SKOV-3 ovarian adenocarcinoma cells. In comparison to the parental SKOV-3 cell line, SKOV-3/LN403 has a higher rate of proliferation, is more invasive and exhibits greater resistance to paclitaxel. Subsequently, a novel animal model of OC lymphatic metastasis was developed with SKOV-3/LN403 cells and a high incidence of positive metastatic lymph nodes, peritoneal dissemination and bloody ascites were observed, which mimicked the clinical outcome of patients with OC. Analysis of the gene expression profiles of SKOV-3 and SKOV-3/LN403 cells identified several genes and pathways that may be involved in lymphatic metastasis of OC. The induction of focal adhesion kinase expression provides a potential therapeutic target for OC lymphatic metastasis.

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Role of Focal Adhesion Kinase in Regulating YB–1–Mediated Paclitaxel Resistance in Ovarian Cancer

Abstract: We have identified a novel pathway whereby FAK inhibition with VS-6063 overcomes YB-1-mediated paclitaxel resistance by an AKT-dependent pathway. These findings have implications for clinical trials aimed at targeting FAK.

Cited by 160 publications

References 40 publications

Exosome-derived microRNAs contribute to prostate cancer chemoresistance

Exosome-derived microRNAs contribute to prostate cancer chemoresistance

Downregulation of HNF1 homeobox B is associated with drug resistance in ovarian cancer

Identification of lymphatic metastasis-associated genes in a metastatic ovarian cancer cell line

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