Abstract
Therapy-resistant pancreatic cancer (PC) cells play a crucial role in tumor relapse, recurrence, and metastasis. Recently, we showed the anti-PC potential of an array of seaweed polyphenols and identified efficient drug deliverables. Herein, we investigated the benefit of one such deliverable, Hormophysa triquerta polyphenol (HT-EA), in regulating the dissemination physiognomy of therapy-resistant PC cells in vitro,and residual PC in vivo. Human PC cells exposed to ionizing radiation (IR), with/without HT-EA pre-treatment were examined for the alterations in the tumor invasion/metastasis (TIM) transcriptome (93 genes, QPCR-profiling). Utilizing a mouse model of residual PC, we investigated the benefit of HT-EA in the translation regulation of crucial TIM targets (TMA-IHC). Radiation activated 30, 50, 15, and 38 TIM molecules in surviving Panc-1, Panc-3.27, BxPC3, and MiaPaCa-2 cells. Of these, 15, 44, 12, and 26 molecules were suppressed with HT-EA pre-treatment. CXCR4 and COX2 exhibited cell-line-independent increases after IR, and was completely suppressed with HT-EA, across all PC cells. HT-EA treatment resulted in translational repression of IR-induced CXCR4, COX2, β-catenin, MMP9, Ki-67, BAPX, PhPT-1, MEGF10, and GRB10 in residual PC. Muting CXCR4 or COX2 regulated the migration/invasion potential of IR-surviving cells, while forced expression of CXCR4 or COX2 significantly increased migration/invasion capabilities of PC cells. Further, treatment with HT-EA significantly inhibited IR-induced and CXCR4/COX2 forced expression-induced PC cell migration/invasion. This study (i) documents the TIM blueprint in therapy-resistant PC cells, (ii) defines the role of CXCR4 and COX2 in induced metastatic potential, and (iii) recognizes the potential of HT-EA in deterring the CXCR4/COX2-dependent dissemination destiny of therapy-resistant residual PC cells.
Highlights
With an expected 53,070 new cases in 2016, pancreatic cancer (PC) is one of the major causes of cancer death in the United States [1]
To define the radio-responsive tumor invasion/ metastasis (TIM)-related signaling in PC cells, we investigated the alterations in mRNA levels for 93 well-characterized TIM molecules (Table S1) in genetically diverse human PC cells exposed to clinical radiation therapy (RT)
To investigate whether Hormophysa triquerta polyphenol (HT-EA) regulates radiationinduced common targets (CXCR4, COX2) and other critical proteins (β-catenin, MMP9, Ki-67, NKX3.2, PhPT1, GRB10) that are instrumental in PC progression after therapy, we examined their alterations in PC cells that were selectively exposed to RT, with or without a daily dose of HT-EA
Summary
With an expected 53,070 new cases in 2016, pancreatic cancer (PC) is one of the major causes of cancer death in the United States [1]. The use of radiation therapy (RT) in PC treatment is multi-fold: (i) RT after surgery prevents tumor relapse or recurrence, (ii) RT before surgery, along with chemotherapy, shrinks and makes removing borderline resectable tumors easier, (iii) RT can be the main treatment, combined with chemotherapy, for locally advanced and unresectable cancers; (iv) RT relieves pain in patients with advanced cancers, and; (iv) RT can be www.impactjournals.com/oncotarget used as the prime modality for people who are not healthy enough for other treatments [3, 4]. Clinical trials that investigated the benefit of RT, either alone or as part of chemo-RT, have shown equivocal clinical outcomes in patients with PC [4, 5]. Radio-sensitizing PC cells could significantly benefit patients diagnosed with resectable disease who suffer from local and/or distant failure post-resection [7, 8]. The need to defeat PC’s induced radio-resistance and to potentiate therapeutic radiation highlights the necessity of elucidating the underlying mechanisms of PC
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