title: The flavonoid apigenin reduces prostate cancer CD44(+) stem cell survival and migration through PI3K/Akt/NF-κB signaling.
abstract: OBJECTIVE
  Cancer stem cells (CSCs) are involved in drug resistance, metastasis and recurrence of cancers. The efficacy of apigenin on cell survival, apoptosis, migration and stemness properties were analyzed in CSCs.
  
  
  METHODS
  Prostate CSCs (CD44(+)) were isolated from human prostate cancer (PCa) PC3 cells using a magnetic-activated cell sorting system. PC3 and CSCs were treated with various concentrations of apigenin, docetaxel and their combinations for 48h.
  
  
  RESULTS
  Apigenin dose dependently inhibited CSCs and PC3 cell survival, and this was accompanied with a significant increase of p21 and p27. Apigenin induced apoptosis via an extrinsic caspase-dependent pathway by upregulating the mRNA expressions of caspases-8, -3 and TNF-α, but failed to regulate the intrinsic pathway as determined by the Bax, cytochrome c (Cyt-c) and APAF-1 in CSCs. In contrary to CSCs, apigenin induced intrinsic apoptosis pathway as evidenced by the induction of Bax, Cyt-c and caspase-3 while caspase-8, TNF-α and Bcl-2 levels remained unchanged in PC3 cells. The flavonoid strongly suppressed the migration rate of CSCs compared to untreated cells. Significant downregulation of matrix metallopeptidases-2, -9, Snail and Slug exhibits the ability of apigenin treatment to suppress invasion. The expressions of NF-κB p105/p50, PI3K, Akt and the phosphorylation of pAkt were decreased after apigenin treatment. Moreover, apigenin treatment significantly reduced pluripotency marker Oct3/4 protein expression which might be associated with the down-regulation of PI3K/Akt/NF-κB signaling.
  
  
  CONCLUSIONS
  Our data indicated that, apigenin could be a useful compound to prevent proliferation and migration of cancer cells as well as CSCs.
authors: Department of Medical Biology, School of Medicine, Trakya University, Balkan Campus, Edirne, Turkey. Electronic address: suaterdogan@trakya.edu.tr.
authors: Suat
authors: S
authors: Erdogan
authors: Department of Medical Biology, School of Medicine, Trakya University, Balkan Campus, Edirne, Turkey.
authors: Oguzhan
authors: O
authors: Doganlar
authors: Department of Medical Biology, School of Medicine, Trakya University, Balkan Campus, Edirne, Turkey.
authors: Zeynep B
authors: ZB
authors: Doganlar
authors: Department of Medical Biology, School of Medicine, Trakya University, Balkan Campus, Edirne, Turkey.
authors: Riza
authors: R
authors: Serttas
authors: Department of Medical Biology, School of Medicine, Trakya University, Balkan Campus, Edirne, Turkey.
authors: Kader
authors: K
authors: Turkekul
authors: Department of Biochemistry, School of Medicine, Trakya University, Balkan Campus, Edirne, Turkey.
authors: Ilker
authors: I
authors: Dibirdik
authors: Department of Histology and Embryology, School of Medicine, İstanbul University, Capa, Istanbul, Turkey.
authors: Ayhan
authors: A
authors: Bilir
mesh_terms: D047310:Apigenin / Q000494:pharmacology*; D017209:Apoptosis; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002470:Cell Survival; D006801:Humans; D018960:Hyaluronan Receptors / Q000276:immunology*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000276:immunology* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D018960:Hyaluronan Receptors; D016328:NF-kappa B; D047310:Apigenin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: Apigenin; CD44(+); CSCs; Docetaxel; PC3; Prostate cancer; Stem cells