Ran is a potential therapeutic target for cancer cells with molecular changes associated with activation of the PI3K/Akt/mTORC1 and Ras/MEK/ERK pathways

Yuen, Hiu-Fung, Chan, Kai-Kui, Grills, Claire, Murray, James T., Platt-Higgins, Angela, Eldin, Osama S., O'Byrne, Kenneth J., Janne, Pasi, Fennell, Dean A., Johnston, Patrick G., Rudland, Philip S., & El-Tanani, Mohamed (2012) Ran is a potential therapeutic target for cancer cells with molecular changes associated with activation of the PI3K/Akt/mTORC1 and Ras/MEK/ERK pathways. Clinical Cancer Research, 18(2), pp. 380-391.

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Purpose Cancer cells have been shown to be more susceptible to Ran knockdown than normal cells. We now investigate whether Ran is a potential therapeutic target of cancers with frequently found mutations that lead to higher Ras/MEK/ERK [mitogen-activated protein/extracellular signal-regulated kinase (ERK; MEK)] and phosphoinositide 3-kinase (PI3K)/Akt/mTORC1 activities.

Experimental Design Apoptosis was measured by flow cytometry [propidium iodide (PI) and Annexin V staining] and MTT assay in cancer cells grown under different conditions after knockdown of Ran. The correlations between Ran expression and patient survival were examined in breast and lung cancers.

Results Cancer cells with their PI3K/Akt/mTORC1 and Ras/MEK/ERK pathways inhibited are less susceptible to Ran silencing-induced apoptosis. K-Ras-mutated, c-Met-amplified, and Pten-deleted cancer cells are also more susceptible to Ran silencing-induced apoptosis than their wild-type counterparts and this effect is reduced by inhibitors of the PI3K/Akt/mTORC1 and MEK/ERK pathways. Overexpression of Ran in clinical specimens is significantly associated with poor patient outcome in both breast and lung cancers. This association is dramatically enhanced in cancers with increased c-Met or osteopontin expression, or with oncogenic mutations of K-Ras or PIK3CA, all of which are mutations that potentially correlate with activation of the PI3K/Akt/mTORC1 and/or Ras/MEK/ERK pathways. Silencing Ran also results in dysregulation of nucleocytoplasmic transport of transcription factors and downregulation of Mcl-1 expression, at the transcriptional level, which are reversed by inhibitors of the PI3K/Akt/mTORC1 and MEK/ERK pathways.

Conclusion Ran is a potential therapeutic target for treatment of cancers with mutations/changes of expression in protooncogenes that lead to activation of the PI3K/Akt/mTORC1 and Ras/MEK/ERK pathways. ©2011 AACR.

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ID Code: 65784
Item Type: Journal Article
Refereed: Yes
Additional Information: Articles free to read on journal website after 12 months
Additional URLs:
Keywords: K ras protein, mammalian target of rapamycin complex 1, messenger RNA, mitogen activated protein kinase, osteopontin, phosphatidylinositol 3 kinase, protein kinase B, protein mcl 1, Ran protein, Ras protein, scatter factor receptor, apoptosis, article, breast cancer, c MET gene, cancer cell culture, cancer prognosis, cancer survival, cell immortalization, controlled study, enzyme activation, flow cytometry, gene, gene deletion, gene expression regulation, gene mutation, gene overexpression, gene silencing, gene targeting, human, human cell, human tissue, intracellular signaling, lung cancer, mcl 1 gene, molecular pathology, molecularly targeted therapy, nucleocytoplasmic transport, nucleotide sequence, oncogene, oncogene K ras, osteopontin gene, PIK3CA gene, priority journal, Pten gene, Ran gene, transcription regulation, Active Transport, Cell Nucleus, Breast Neoplasms, Carcinoma, Cell Line, Tumor, Female, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Humans, Kaplan-Meier Estimate, Lung Neoplasms, MAP Kinase Signaling System, Mitogen-Activated Protein Kinases, Mutation, Neoplasm Invasiveness, Phosphatidylinositol 3-Kinases, Proteins, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-bcl-2, Proto-Oncogene Proteins c-met, PTEN Phosphohydrolase, ran GTP-Binding Protein, ras Proteins, RNA Interference, Signal Transduction, Transcription, Genetic
DOI: 10.1158/1078-0432.CCR-11-2035
ISSN: 1078-0432
Divisions: Current > Schools > School of Biomedical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright 2012 American Association for Cancer Research
Deposited On: 08 Jan 2014 04:26
Last Modified: 29 Jan 2015 05:08

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