title: Cigarette smoke promotes drug resistance and expansion of cancer stem cell-like side population.
abstract: It is well known that many patients continue to smoke cigarettes after being diagnosed with cancer. Although smoking cessation has typically been presumed to possess little therapeutic value for cancer, a growing body of evidence suggests that continued smoking is associated with reduced efficacy of treatment and a higher incidence of recurrence. We therefore investigated the effect of cigarette smoke condensate (CSC) on drug resistance in the lung cancer and head and neck cancer cell lines A549 and UMSCC-10B, respectively. Our results showed that CSC significantly increased the cellular efflux of doxorubicin and mitoxantrone. This was accompanied by membrane localization and increased expression of the multi-drug transporter ABCG2. The induced efflux of doxorubicin was reversed upon addition of the specific ABCG2 inhibitor Fumitremorgin C, confirming the role of ABCG2. Treatment with CSC increased the concentration of phosphorylated Akt, while addition of the PI3K inhibitor LY294002 blocked doxorubicin extrusion, suggesting that Akt activation is required for CSC-induced drug efflux. In addition, CSC was found to promote resistance to doxorubicin as determined by MTS assays. This CSC-induced doxurbicin-resistance was mitigated by mecamylamine, a nicotinic acetylcholine receptor inhibitor, suggesting that nicotine is at least partially responsible for the effect of CSC. Lastly, CSC increased the size of the side population (SP), which has been linked to a cancer stem cell-like phenotype. In summary, CSC promotes chemoresistance via Akt-mediated regulation of ABCG2 activity, and may also increase the proportion of cancer stem-like cells, contributing to tumor resilience. These findings underscore the importance of smoking cessation following a diagnosis of cancer, and elucidate the mechanisms of continued smoking that may be detrimental to treatment.
authors.affiliation: Division of Head and Neck Surgery, Department of Surgery, University of California San Diego, San Diego, California, United States of America.
authors.forename: Yi
authors.initials: Y
authors.lastname: An
authors.forename: Alan
authors.initials: A
authors.lastname: Kiang
authors.forename: Jay Patrick
authors.initials: JP
authors.lastname: Lopez
authors.forename: Selena Z
authors.initials: SZ
authors.lastname: Kuo
authors.forename: Michael Andrew
authors.initials: MA
authors.lastname: Yu
authors.forename: Eric L
authors.initials: EL
authors.lastname: Abhold
authors.forename: Jocelyn S
authors.initials: JS
authors.lastname: Chen
authors.forename: Jessica
authors.initials: J
authors.lastname: Wang-Rodriguez
authors.forename: Weg M
authors.initials: WM
authors.lastname: Ongkeko
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008942:Mitoxantrone / Q000378:metabolism / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000502:physiology; D009538:Nicotine / Q000494:pharmacology; D018722:Nicotinic Agonists / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D058985:Side-Population Cells / Q000187:drug effects* / Q000502:physiology; D015398:Signal Transduction; D012906:Smoke; D014026:Nicotiana / Q000737:chemistry*
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000903:Antibiotics, Antineoplastic; D002867:Chromones; D004317:Doxorubicin; D008942:Mitoxantrone; D009025:Morpholines; D009363:Neoplasm Proteins; D009538:Nicotine; D018722:Nicotinic Agonists; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D012906:Smoke; C116614:ABCG2 protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one