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Targeting Integrin‐linked Kinase with Small‐interfering RNA Suppresses Invasion and Metastasis in Cisplatin‐Resistant Ovarian Cancer
Author(s) -
ReyesGonzález Jeyshka M.,
Báez Perla,
Valiyeva Fatma,
VivasMejía Pablo E.
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.934.18
Subject(s) - integrin linked kinase , cisplatin , ovarian cancer , small interfering rna , cancer research , metastasis , gene silencing , cancer , kinase , medicine , chemistry , biology , chemotherapy , transfection , cell culture , cell cycle , microbiology and biotechnology , cyclin dependent kinase 2 , biochemistry , gene , genetics
Ovarian cancer has the highest mortality rate among gynecological cancers. It continues to be characterized by metastatic bulky disease burden, which presents a major clinical challenge. Advanced disease is often treated with surgery, followed by platinum‐based chemotherapy such as cisplatin. Unfortunately, the majority of ovarian cancer patients become resistant to cisplatin, and relapse. Therefore, the identification of targets that link metastasis and chemoresistance is urgently needed to develop novel and effective strategies for ovarian cancer treatment. Integrin‐linked kinase (ILK), a serine/threonine kinase and adaptor protein, has been shown to play crucial roles in cancer progression, epithelial‐mesenchymal transition (EMT), angiogenesis, and metastasis. Our previous findings indicate that cisplatin‐resistant ovarian cancer cells (A2780CP20 and OV90CIS) express higher levels of phosphorylated ILK (p‐ILK) protein when compared to their parental counterparts (A2780 and OV90, respectively). Targeting ILK with small‐interfering RNAs (siRNAs) significantly reduced the invasive ability of A2780CP20 and OV90CIS cells in vitro (85.5% reduction; p<0.0001 and 61.6% reduction; p<0.0001, respectively). Therefore, to investigate the effects of ILK silencing in vivo , Control‐siRNA or ILK‐siRNA were encapsulated into DOPC‐DSPE‐PEG‐2000‐nanoliposomes. First, to assess the efficacy of the nanoliposomal siRNAs to silence their target in vivo , cisplatin‐resistant ovarian cancer cells (A2780CP20) were intraperitoneally injected into nude mice. Three weeks after tumor implantation, mice were treated twice with either Control‐siRNA or ILK‐siRNA nanoliposomes. ILK protein levels were significantly downregulated by ILK‐siRNA compared to Control‐siRNA, as evident in Western blot analysis (40% reduction; p<0.05). Next, to assess the involvement of ILK in metastasis in vivo , A2780CP20 cells were intraperitoneally injected into nude mice. Seven days after cell inoculation, mice received a weekly dose of either Control‐siRNA or ILK‐siRNA nanoliposomes. At the end of the treatment period, ILK‐siRNA significantly reduced the number of tumor nodules compared to Control‐siRNA (48% reduction; p<0.01). No obvious toxicity during therapy was observed. These results indicate that silencing ILK is a promising therapeutic approach for advanced and chemoresistant ovarian cancer. Further studies are required to investigate the biologic and molecular roles of ILK downstream targets in cisplatin‐resistant ovarian cancer. Support or Funding Information This project was supported in part by the RTRN (U54MD008149) grant to PEVM, institutional seed funds from the University of Puerto Rico, Comprehensive Cancer Center (PEVM), and National Institute of Health, Minority Biomedical Research Support (MBRS) RISE Grant Number R25‐GM061838 (JMRG).