title: Nicotine promotes apoptosis resistance of breast cancer cells and enrichment of side population cells with cancer stem cell-like properties via a signaling cascade involving galectin-3, α9 nicotinic acetylcholine receptor and STAT3.
abstract: Nicotine, a main addictive compound in tobacco smoke, has been linked to promotion and progression of lung, head and neck, pancreatic, and breast cancers, but the detailed mechanisms of cancer progression remain elusive. Here, we show that nicotine induces the expression of galectin-3 (an anti-apoptotic β-galactoside-binding lectin) in breast cancer cell line and in primary tumors from breast cancer patients. Nicotine-induced up regulation of galectin-3 is due to an increased expression of α9 isoform of nicotinic acetylcholine receptor (α9nAChR), which activates transcription factor STAT3 that in turn, physically binds to galectin-3 (LGALS3) promoter and induces transcription of galectin-3. Intracellular galectin-3 increased mitochondrial integrity and suppressed chemotherapeutic-induced apoptosis of breast cancer cell. Moreover, nicotine-induced enrichment of side population cells with cancer stem cell-like properties was modulated by galectin-3 expression and could be significantly reduced by transient knock down of LGALS3 and its upstream signaling molecules STAT3 and α9nAChR. Thus, galectin-3 or its upstream signaling molecule STAT3 or α9nAChR could be a potential target to prevent nicotine-induced chemoresistance in breast cancer.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Prasun
authors.initials: P
authors.lastname: Guha
authors.forename: Gargi
authors.initials: G
authors.lastname: Bandyopadhyaya
authors.forename: Swamy K
authors.initials: SK
authors.lastname: Polumuri
authors.forename: Saranya
authors.initials: S
authors.lastname: Chumsri
authors.forename: Padmaja
authors.initials: P
authors.lastname: Gade
authors.forename: Dhananjaya V
authors.initials: DV
authors.lastname: Kalvakolanu
authors.forename: Hafiz
authors.initials: H
authors.lastname: Ahmed
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D053938:DNA Fragmentation; D037502:Galectin 3 / Q000096:biosynthesis; D006801:Humans; D007150:Immunohistochemistry; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D011978:Receptors, Nicotinic / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D058985:Side-Population Cells; D015398:Signal Transduction / Q000187:drug effects*; D014162:Transfection
chemical_list: C498540:CHRNA9 protein, human; D037502:Galectin 3; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D009538:Nicotine