title: Inhibition of PI3K signaling triggered apoptotic potential of curcumin which is hindered by Bcl-2 through activation of autophagy in MCF-7 cells.
abstract: Curcumin is a natural anti-cancer agent derived from turmeric (Curcuma longa). Curcumin triggers intrinsic apoptotic cell death by activating mitochondrial permeabilization due to the altered expression of pro- and anti-apoptotic Bcl-2 family members. Phosphoinositol-3-kinase (PI3K) and Akt, key molecular players in the survival mechanism, have been shown to be associated with the Bcl-2 signaling cascade; therefore, evaluating the therapeutic efficiency of drugs that target both survival and the apoptosis mechanism has gained importance in cancer therapy. We found that Bcl-2 overexpression is a limiting factor for curcumin-induced apoptosis in highly metastatic MCF-7 breast cancer cells. Forced overexpression of Bcl-2 also blocked curcumin-induced autophagy in MCF-7 cells, through its inhibitory interactions with Beclin-1. Pre-treatment of PI3K inhibitor LY294002 enhanced curcumin-induced cell death, apoptosis, and autophagy via modulating the expression of Bcl-2 family members and autophagosome formation in MCF-7 breast cancer cells. Atg7 silencing further increased apoptotic potential of curcumin in the presence or absence of LY294002 in wt and Bcl-2+ MCF-7 cells. The findings of this study support the hypothesis that blocking the PI3K/Akt pathway may further increased curcumin-induced apoptosis and overcome forced Bcl-2 expression level mediated autophagic responses against curcumin treatment in MCF-7 cells.
authors.affiliation: Department of Molecular Biology and Genetics, Istanbul Kültür University, Atakoy Campus, 34156 Bakirkoy-Istanbul, Turkey.
authors.forename: Yunus
authors.initials: Y
authors.lastname: Akkoç
authors.affiliation: Department of Molecular Biology and Genetics, Istanbul Kültür University, Atakoy Campus, 34156 Bakirkoy-Istanbul, Turkey.
authors.forename: Özge
authors.initials: Ö
authors.lastname: Berrak
authors.affiliation: Department of Molecular Biology and Genetics, Istanbul Kültür University, Atakoy Campus, 34156 Bakirkoy-Istanbul, Turkey. Electronic address: d.arisan@iku.edu.tr.
authors.forename: Elif Damla
authors.initials: ED
authors.lastname: Arısan
authors.affiliation: Department of Molecular Biology and Genetics, Istanbul Kültür University, Atakoy Campus, 34156 Bakirkoy-Istanbul, Turkey.
authors.forename: Pınar
authors.initials: P
authors.lastname: Obakan
authors.affiliation: Department of Molecular Biology and Genetics, Istanbul Kültür University, Atakoy Campus, 34156 Bakirkoy-Istanbul, Turkey.
authors.forename: Ajda
authors.initials: A
authors.lastname: Çoker-Gürkan
authors.affiliation: Department of Molecular Biology and Genetics, Istanbul Kültür University, Atakoy Campus, 34156 Bakirkoy-Istanbul, Turkey.
authors.forename: Narçin
authors.initials: N
authors.lastname: Palavan-Ünsal
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D000071193:Autophagy-Related Protein 7; D048430:Cell Shape / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D003474:Curcumin / Q000494:pharmacology*; D005260:Female; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D061986:MCF-7 Cells; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D044764:Ubiquitin-Activating Enzymes / Q000378:metabolism
chemical_list: D000071193:Autophagy-Related Protein 7; D002867:Chromones; D003474:Curcumin; D008869:Microtubule-Associated Proteins; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D044764:Ubiquitin-Activating Enzymes; C477012:MAP1LC3A protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C509349:ATG7 protein, human
keywords: Apoptosis; Breast cancer; Curcumin; LY294002; PI3K