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  • Being an in vitro study it has some


    Being an in vitro study it has some limitations before it can be translated to the clinic. We investigated several cell models in which the results on EMT or ACF are not always identical. We selected the models to be complementary, we saw that EMT induction by stimulation (TGF-β1 or CoCl2) is functional not very different from the drug resistance models although certain molecular features are not exactly the same. The same variation is to be expected when in vivo different microenvironmental factors induce a cancer dextromethorphan hydrobromide to EMT. We then looked for features that could be repeated in the different models of aggressive cancer. Our conclusions are therefore based on the linkage of transcriptome data with alterations in cellular programs EMT and UPR. Although these findings are very suggestive for a causal relationship, additional mechanistic studies are needed to definitely confirm our hypotheses. However, recent studies have shown that PERK/eIF2a activation is necessary for EMT cells to invade and metastasize providing a link between the two concepts [19]. Moreover, ATF4 knock-down impedes hypoxia induced EMT in gastric cancer cell lines [16]. From these and other studies, it is clear that acriflavine is an interesting compound with pleiotropic anticancer effects [21], [22], [43]. Its past systemic use in the clinical setting as an antibiotic without any major toxicity reported encourages further development of the drug for cancer treatment [44]. We hypothesize that ACF pushes the cancer cell to an epithelial state, blocking the development of drug resistance and prolonging the time frame over which a drug can have its effect on the tumor and so increasing its effectiveness. However, at present no preparation for clinical use is available and dextromethorphan hydrobromide the interest of the industry in off-patent drugs is limited [45]. We believe studies like these should prompt non-profit institutions to take initiatives that allow repurposing acriflavine for animal and clinical testing in oncology.
    Acknowledgements We acknowledge our use of the gene set enrichment analysis, GSEA software, and Molecular Signature Database (MSigDB) (Subramanian, Tamayo, et al. (2005), PNAS 102, 15545-15550, We thank prof. Landowski for providing us with the gemcitabine resistant MiaPaCa-2 cell lines and prof. Stein Aerts and his colleagues for the discussion on the iRegulon results. CV holds a mandate as Senior Clinical Investigator of the Research Foundation - Flanders (Belgium) (FWO). This study was partly supported by a research grant from “Kom op tegen Kanker” Belgium and VUYLSTEKE-FLIPTS FONDS LEVERKANKER.
    Introduction PTEN is a powerful tumor suppressor gene that is frequently mutated in human cancer (Li et al., 1997, Steck et al., 1997, Teng et al., 1997). Germline mutations of PTEN are associated with tumor-susceptibility diseases, such as Cowden syndrome, which is characterized by multiple hamartomas (Liaw et al., 1997, Nelen et al., 1997). The role of PTEN as a potent tumor suppressor has been demonstrated in many animal models, where Pten deletion leads to development of various types of tumors that mimic the spectrum of human cancers associated with PTEN mutations (Di Cristofano et al., 1998, Podsypanina et al., 1999, Stambolic et al., 2000). Pten loss also results in neurological defects and metabolic disorders (Gasser, 2007, Stiles et al., 2004, Stiles et al., 2006), suggesting that PTEN function is not limited to tumor suppression. PTEN is essential for embryonic development as homozygous Pten deletion results in developmental defects and embryonic lethality (Di Cristofano et al., 1998, Podsypanina et al., 1999, Suzuki et al., 1998). These findings all demonstrate the importance of PTEN in a diversity of biological processes including embryonic development, tissue homeostasis, metabolism, and tumor suppression.