title: Lycopene synergistically enhances quinacrine action to inhibit Wnt-TCF signaling in breast cancer cells through APC.
abstract: We previously reported that quinacrine (QC) has anticancer activity against breast cancer cells. Here, we examine the mechanism of action of QC and its ability to inhibit Wnt-TCF signaling in two independent breast cancer cell lines. QC altered Wnt-TCF signaling components by increasing the levels of adenomatous polyposis coli (APC), DAB2, GSK-3β and axin and decreasing the levels of β-catenin, p-GSK3β (ser 9) and CK1. QC also reduced the activity of the Wnt transcription factor TCF/LEF and its downstream targets cyclin D1 and c-MYC. Using a luciferase-based Wnt-TCF transcription factor assay, it was shown that APC levels were inversely associated with TCF/LEF activity. Induction of apoptosis and DNA damage was observed after treatment with QC, which was associated with increased expression of APC. The effects induced by QC depend on APC because the inhibition of Wnt-TCF signaling by QC is lost in APC-knockdown cells, and consequently, the extent of apoptosis and DNA damage caused by QC is reduced compared with parental cells. Because we previously showed that QC inhibits topoisomerase, we examined the effect of another topoisomerase inhibitor, etoposide, on Wnt signaling. Interestingly, etoposide treatment also reduced TCF/LEF activity, β-catenin and cyclin D1 levels commensurate with induction of DNA damage and apoptosis. Lycopene, a plant-derived antioxidant, synergistically increased QC activity and inhibited Wnt-TCF signaling in cancer cells without affecting the MCF-10A normal breast cell line. Collectively, the data suggest that QC-mediated Wnt-TCF signal inhibition depends on APC and that the addition of lycopene synergistically increases QC anticancer activity.
authors.affiliation: Cancer Biology Laboratory, Department of KIIT School of Biotechnology, Campus-11, KIIT University, Patia, Bhubaneswar, Orissa  751024, India.
authors.forename: Ranjan
authors.initials: R
authors.lastname: Preet
authors.forename: Purusottam
authors.initials: P
authors.lastname: Mohapatra
authors.forename: Dipon
authors.initials: D
authors.lastname: Das
authors.forename: Shakti R
authors.initials: SR
authors.lastname: Satapathy
authors.forename: Tathagata
authors.initials: T
authors.lastname: Choudhuri
authors.forename: Michael D
authors.initials: MD
authors.lastname: Wyatt
authors.forename: Chanakya N
authors.initials: CN
authors.lastname: Kundu
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016588:Anticarcinogenic Agents / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002338:Carotenoids / Q000494:pharmacology*; D002453:Cell Cycle; D049109:Cell Proliferation; D020552:Comet Assay; D019938:Cyclin D1 / Q000378:metabolism; D004357:Drug Synergism; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D000077276:Lycopene; D011401:Promoter Regions, Genetic; D011796:Quinacrine / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*; D051822:T Cell Transcription Factor 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051820:TCF Transcription Factors; D015534:Trans-Activators / Q000378:metabolism; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay; D051153:Wnt Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: C555337:APC protein, human; D025601:Adenomatous Polyposis Coli Protein; D016588:Anticarcinogenic Agents; D000972:Antineoplastic Agents, Phytogenic; C530104:CCND1 protein, human; D034741:RNA, Small Interfering; D051822:T Cell Transcription Factor 1; D051820:TCF Transcription Factors; C497576:TCF7 protein, human; D015534:Trans-Activators; D051153:Wnt Proteins; D051176:beta Catenin; D019938:Cyclin D1; D002338:Carotenoids; D005047:Etoposide; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D011796:Quinacrine; D000077276:Lycopene