Abstract
BackgroundIdentifying 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.ResultsHuman 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.ConclusionsThese 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.
Highlights
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
Activated autophagy machinery in resistant PC cells after first-line Radiotherapy To better characterize the autophagy phenotype of the PC cells that survive first-line therapy, we examined the transcriptional modulation of autophagy functional regulators ATG3, ATG5, ATG7, ATG12, Toll-like receptors (TLRs)-1, TLR-2, TLR-3, TLR-4, TLR-5, TLR-6, TLR-7, TLR-8, TLR-9, HMGB-1, RAGE, LC3A, light chain 3B (LC3B), Beclin, and MYD88, in genetically diverse human Panc-3.27 and MiaPaCa-2 cells exposed to clinically relevant fractionated radiation (2 Gy/Day for 5 days)
The activated transcription was evident in MiaPaCa-2 cells, the activation of ATG3, HMGB1, RAGE, TLR-1, TLR-2, TLR-3, TLR-6 and TLR-9 were marginal after fractionated irradiation (FIR)
Summary
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. A well-regulated cell survival mechanism, plays a crucial role in the maintenance of normal human physiological processes, including cellular homeostasis, energetic balance, and development [2,3]. We investigated the autophagy-related molecular programming in human PC cells that survive first-line therapy. The molecular orchestration of autophagy is complex and involves more than 30 autophagy-related genes (ATGs) [27,28] Silencing these crucial autophagy drivers significantly inhibits cell growth and colony formation of PC cells [16]. Recognizing a drug-deliverable that regulates basal elevated levels of autophagy, and targets the therapy-associated onset, activation, and maintenance of autophagy would have momentous impact in the mitigation of PC relapse and metastasis, the major hurdles to curing PC. This study investigates the autophagy-inhibiting potential of anti-oxidant rich seaweed polyphenol fractions
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