Open AccessiNOS Regulates the Therapeutic Response of Pancreatic Cancer Cells to Radiotherapy
Author(s) -
Patrícia M. R. Pereira,
Kimberly J. Edwards,
Komal Mandleywala,
Lukas M. Carter,
Freddy E. Escorcia,
Luís Felipe Campesato,
Mike Cornejo,
Lolkje Abma,
Abu Akeel Mohsen,
Christine A. Iacobuzio-Donahue,
Taha Merghoub,
Jason S. Lewis
Publication year - 2020
Publication title -
cancer research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.103
H-Index - 449
eISSN - 1538-7445
pISSN - 0008-5472
DOI - 10.1158/0008-5472.can-19-2991
Subject(s) - radiation therapy , pancreatic cancer , cancer research , tumor microenvironment , medicine , nitric oxide synthase , pancreatic tumor , cancer , nitric oxide , cancer cell , pathology , tumor cells
Pancreatic ductal adenocarcinoma (PDAC) is highly resistant to radiotherapy, chemotherapy, or a combination of these modalities, and surgery remains the only curative intervention for localized disease. Although cancer-associated fibroblasts (CAF) are abundant in PDAC tumors, the effects of radiotherapy on CAFs and the response of PDAC cells to radiotherapy are unknown. Using patient samples and orthotopic PDAC biological models, we showed that radiotherapy increased inducible nitric oxide synthase (iNOS) in the tumor tissues. Mechanistic in vitro studies showed that, although undetectable in radiotherapy-activated tumor cells, iNOS expression and nitric oxide (NO) secretion were significantly increased in CAFs secretome following radiotherapy. Culture of PDAC cells with conditioned media from radiotherapy-activated CAFs increased iNOS/NO signaling in tumor cells through NF-κB, which, in turn, elevated the release of inflammatory cytokines by the tumor cells. Increased NO after radiotherapy in PDAC contributed to an acidic microenvironment that was detectable using the radiolabeled pH (low) insertion peptide (pHLIP). In murine orthotopic PDAC models, pancreatic tumor growth was delayed when iNOS inhibition was combined with radiotherapy. These data show the important role that iNOS/NO signaling plays in the effectiveness of radiotherapy to treat PDAC tumors. SIGNIFICANCE: A radiolabeled pH-targeted peptide can be used as a PET imaging tool to assess therapy response within PDAC and blocking iNOS/NO signaling may improve radiotherapy outcomes.