title: Novel adjuvants from seaweed impede autophagy signaling in therapy-resistant residual pancreatic cancer.
abstract: BACKGROUND
  Identifying the drug-deliverables that target autophagy is crucial to finding a cure for pancreatic cancer (PC), as activated autophagy is associated with poor patient outcomes. Our recent studies recognized the anti-PC potential of an antioxidant-rich collection of seaweed polyphenols and identified potential compounds for the treatment of PC. Accordingly, we investigated whether such compounds could regulate autophagy in therapy-resistant PC cells in vitro and in residual PC in vivo.
  
  
  RESULTS
  Human Panc-3.27 and MiaPaCa-2 cells were exposed to fractionated irradiation (FIR) with/without ethyl acetate (EA) polyphenol from Spatoglossum asperum (SA-EA), Padina tetrastromatica (PT-EA), or Hormophysa triquerta (HT-EA). The cells were subjected to QPCR to examine transcriptional alterations in the following autophagy functional regulators: ATG3, ATG5, ATG7, ATG12, LC3A, LC3B, Beclin, Myd88, HMGB1, Rage, and TLRs 1-9. Using a clinically relevant mouse model of residual PC, we use tissue microarray (TMA) and immunohistochemistry (IHC) procedures to investigate the potential of polyphenol(s) to target ATG3, ATG5, ATG12, LC3A, LC3B, BECN1, and SURIVIN after clinical radiotherapy. Radiation significantly increased the transcription of autophagy functional regulators in both cell lines. Seaweed polyphenols completely suppressed the transcription of all investigated autophagy regulators in both cell-lines. Gene silencing approach defined the role of LC3B in radiation-induced cell survival in this setting. TMA-IHC analysis revealed the complete regulation of ATG3, ATG5, ATG12, LC3A, LC3B, BECN1, and SURVIVIN in residual PC following SA-EA, PT-EA, and HT-EA treatment.
  
  
  CONCLUSIONS
  These data demonstrate the autophagy blue print in therapy-resistant PC cells for the first time. Moreover, the data strongly suggest that the selected polyphenols could serve as effective adjuvants for current PC treatment modalities and may inhibit tumor relapse by comprehensively targeting therapy-orchestrated autophagy in residual cells.
authors.affiliation: Department of Marine Sciences, Center of Advanced Study in Marine Biology, Annamalai University, Parangipettai, TN, India. saravind@ouhsc.edu.|Stephenson Cancer Center, Oklahoma City, OK, USA. saravind@ouhsc.edu.
authors.forename: Sheeja
authors.initials: S
authors.lastname: Aravindan
authors.affiliation: Department of Radiation Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. sramraj@ouhsc.edu.
authors.forename: Satish Kumar
authors.initials: SK
authors.lastname: Ramraj
authors.affiliation: Department of Marine Sciences, Center of Advanced Study in Marine Biology, Annamalai University, Parangipettai, TN, India. drstscas@yahoo.com.
authors.forename: Somasundaram T
authors.initials: ST
authors.lastname: Somasundaram
authors.affiliation: Department of Radiation Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. naravind@ouhsc.edu.
authors.forename: Natarajan
authors.initials: N
authors.lastname: Aravindan
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000503:physiopathology; D000459:Phaeophyceae / Q000737:chemistry*; D012624:Seaweed / Q000737:chemistry*; D015398:Signal Transduction / Q000187:drug effects*; D014183:Transplantation, Heterologous
chemical_list: D000276:Adjuvants, Immunologic