title: Targeting proapoptotic protein BAD inhibits survival and self-renewal of cancer stem cells.
abstract: Emerging evidence suggests that the resistance of cancer stem cells (CSC) to many conventional therapies is one of the major limiting factors of cancer therapy efficacy. Identification of mechanisms responsible for survival and self-renewal of CSC will help design new therapeutic strategies that target and eliminate both differentiated cancer cells and CSC. Here we demonstrated the potential role of proapoptotic protein BAD in the biology of CSC in melanoma, prostate and breast cancers. We enriched CD44(+)/CD24(-) cells (CSC) by tumorosphere formation and purified this population by FACS. Both spheres and CSC exhibited increased potential for proliferation, migration, invasion, sphere formation, anchorage-independent growth, as well as upregulation of several stem cell-associated markers. We showed that the phosphorylation of BAD is essential for the survival of CSC. Conversely, ectopic expression of a phosphorylation-deficient mutant BAD induced apoptosis in CSC. This effect was enhanced by treatment with a BH3-mimetic, ABT-737. Both pharmacological agents that inhibit survival kinases and growth factors that are involved in drug resistance delivered their respective cytotoxic and protective effects by modulating the BAD phosphorylation in CSC. Furthermore, the frequency and self-renewal capacity of CSC was significantly reduced by knocking down the BAD expression. Consistent with our in vitro results, significant phosphorylation of BAD was found in CD44(+) CSC of 83% breast tumor specimens. In addition, we also identified a positive correlation between BAD expression and disease stage in prostate cancer, suggesting a role of BAD in tumor advancement. Our studies unveil the role of BAD in the survival and self-renewal of CSC and propose BAD not only as an attractive target for cancer therapy but also as a marker of tumor progression.
authors.affiliation: Laboratory of Genetic Medicine and Immunology, Weill Cornell Medical College in Qatar, Education City-Qatar Foundation, Doha 24144, Qatar.
authors.forename: K S R
authors.initials: KS
authors.lastname: Sastry
authors.affiliation: Cancer Research Centre, Qatar Biomedical Research Institute, Qatar Foundation, Doha, Qatar.
authors.forename: M A
authors.initials: MA
authors.lastname: Al-Muftah
authors.affiliation: Shanghai Key Laboratory of Gastric Neoplasms, Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People's Republic of China.
authors.forename: Pu
authors.initials: P
authors.lastname: Li
authors.affiliation: Cancer Research Centre, Qatar Biomedical Research Institute, Qatar Foundation, Doha, Qatar.
authors.forename: M K
authors.initials: MK
authors.lastname: Al-Kowari
authors.affiliation: Translation Medicine Division, Sidra Medical and Research Centre, Doha, Qatar.
authors.forename: E
authors.initials: E
authors.lastname: Wang
authors.affiliation: Translation Medicine Division, Sidra Medical and Research Centre, Doha, Qatar.
authors.forename: A
authors.initials: A
authors.lastname: Ismail Chouchane
authors.affiliation: Laboratory of Genetic Medicine and Immunology, Weill Cornell Medical College in Qatar, Education City-Qatar Foundation, Doha 24144, Qatar.
authors.forename: D
authors.initials: D
authors.lastname: Kizhakayil
authors.affiliation: 1] Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC, USA [2] College of Science, Alfaisal University, Riyadh 11533, Saudi Arabia.
authors.forename: G
authors.initials: G
authors.lastname: Kulik
authors.affiliation: Research Division, Sidra Medical and Research Center, Doha, Qatar.
authors.forename: F M
authors.initials: FM
authors.lastname: Marincola
authors.affiliation: Cancer Research Centre, Qatar Biomedical Research Institute, Qatar Foundation, Doha, Qatar.
authors.forename: A
authors.initials: A
authors.lastname: Haoudi
authors.affiliation: Laboratory of Genetic Medicine and Immunology, Weill Cornell Medical College in Qatar, Education City-Qatar Foundation, Doha 24144, Qatar.
authors.forename: L
authors.initials: L
authors.lastname: Chouchane
mesh_terms: D017209:Apoptosis; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D014411:Neoplastic Stem Cells / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D011499:Protein Processing, Post-Translational; D051025:bcl-Associated Death Protein / Q000378:metabolism*
chemical_list: C494819:BAD protein, human; D051025:bcl-Associated Death Protein