NO•/RUNX3/kynurenine metabolic signaling enhances disease aggressiveness in pancreatic cancer

Limin Wang; Wei Tang; Shouhui Yang; Peijun He; Jian Wang; Jochen Gaedcke; Philipp Ströbel; Azadeh Azizian; Thomas Ried; Matthias M. Gaida; Harris G. Yfantis; Dong H. Lee; Ashish Lal; Benoit J. Van den Eynde; H. Richard Alexander; B. Michael Ghadimi; Nader Hanna; S. Perwez Hussain

doi:10.1002/ijc.32733

NO^•/RUNX3/kynurenine metabolic signaling enhances disease aggressiveness in pancreatic cancer

Limin Wang
, Wei Tang
, Shouhui Yang
, Peijun He
, Jian Wang
, Jochen Gaedcke
, Philipp Ströbel
, Azadeh Azizian
, Thomas Ried
, Matthias M. Gaida
, Harris G. Yfantis
, Dong H. Lee
, Ashish Lal
, Benoit J. Van den Eynde
, H. Richard Alexander
, B. Michael Ghadimi
, Nader Hanna
, S. Perwez Hussain

Cancer Institute of New Jersey (CINJ), Division of Surgical Oncology, Gastrointestinal

Rutgers, The State University

Research output: Contribution to journal › Article › peer-review

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy and is refractory to available treatments. Delineating the regulatory mechanisms of metabolic reprogramming, a key event in pancreatic cancer progression, may identify candidate targets with potential therapeutic significance. We hypothesized that inflammatory signaling pathways regulate metabolic adaptations in pancreatic cancer. Metabolic profiling of tumors from PDAC patients with a high- (>median, n = 31) and low-NOS2 (inducible nitric oxide synthase; <median, n = 32) mRNA expression was performed. Differentially abundant metabolites were analyzed and linked with patient survival. The functional role of the prognostically significant metabolite and the mechanism of its regulation by NOS2/NO^• (nitric oxide)-mediated signaling pathway was elucidated. The level of kynurenine, a tryptophan metabolite, was associated with high NOS2 expression, and a higher level of kynurenine predicted poor survival in patients (n = 63, p = 0.01). Gene expression analysis in PDAC tumors (n = 63) showed a positive correlation between the expression of NOS2 and the tryptophan/kynurenine pathway genes, including indoleamine-2,3-dioxygenase 1 (IDO1) and several aryl hydrocarbon receptor (AHR)-target genes including NFE2L2 (NRF2), SERPINB2, IL1b, IL6 and IL8, which are implicated in pancreatic cancer. Consistently, treatment of pancreatic cancer cell lines with NO^• donor induced IDO1, kynurenine production and the expression of AHR-target genes. Furthermore, kynurenine treatment enhanced spheroid growth and invasive potential of pancreatic cancer cell lines. Mechanistically, NO^•-induced IDO1/Kynurenine/AHR signaling was mediated by RUNX3 transcription factor. Our findings identified a novel NO^•/RUNX3/Kynurenine metabolic axis, which enhances disease aggressiveness in pancreatic cancer and may have potential translational significance in improving disease outcome.

Original language	American English
Pages (from-to)	3160-3169
Number of pages	10
Journal	International Journal of Cancer
Volume	146
Issue number	11
DOIs	https://doi.org/10.1002/ijc.32733
State	Published - Jun 1 2020

ASJC Scopus subject areas

Oncology
Cancer Research

Keywords

RUNX3
kynurenine
nitric oxide
pancreatic cancer
prognosis
therapeutic targets

Access to Document

10.1002/ijc.32733

Cite this

Wang, L., Tang, W., Yang, S., He, P., Wang, J., Gaedcke, J., Ströbel, P., Azizian, A., Ried, T., Gaida, M. M., Yfantis, H. G., Lee, D. H., Lal, A., Van den Eynde, B. J., Alexander, H. R., Ghadimi, B. M., Hanna, N., & Hussain, S. P. (2020). NO^•/RUNX3/kynurenine metabolic signaling enhances disease aggressiveness in pancreatic cancer. International Journal of Cancer, 146(11), 3160-3169. https://doi.org/10.1002/ijc.32733

@article{c8e402fcff2c4c968ea9bb90cd99544a,

title = "NO•/RUNX3/kynurenine metabolic signaling enhances disease aggressiveness in pancreatic cancer",

abstract = "Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy and is refractory to available treatments. Delineating the regulatory mechanisms of metabolic reprogramming, a key event in pancreatic cancer progression, may identify candidate targets with potential therapeutic significance. We hypothesized that inflammatory signaling pathways regulate metabolic adaptations in pancreatic cancer. Metabolic profiling of tumors from PDAC patients with a high- (>median, n = 31) and low-NOS2 (inducible nitric oxide synthase; • (nitric oxide)-mediated signaling pathway was elucidated. The level of kynurenine, a tryptophan metabolite, was associated with high NOS2 expression, and a higher level of kynurenine predicted poor survival in patients (n = 63, p = 0.01). Gene expression analysis in PDAC tumors (n = 63) showed a positive correlation between the expression of NOS2 and the tryptophan/kynurenine pathway genes, including indoleamine-2,3-dioxygenase 1 (IDO1) and several aryl hydrocarbon receptor (AHR)-target genes including NFE2L2 (NRF2), SERPINB2, IL1b, IL6 and IL8, which are implicated in pancreatic cancer. Consistently, treatment of pancreatic cancer cell lines with NO• donor induced IDO1, kynurenine production and the expression of AHR-target genes. Furthermore, kynurenine treatment enhanced spheroid growth and invasive potential of pancreatic cancer cell lines. Mechanistically, NO•-induced IDO1/Kynurenine/AHR signaling was mediated by RUNX3 transcription factor. Our findings identified a novel NO•/RUNX3/Kynurenine metabolic axis, which enhances disease aggressiveness in pancreatic cancer and may have potential translational significance in improving disease outcome.",

keywords = "RUNX3, kynurenine, nitric oxide, pancreatic cancer, prognosis, therapeutic targets",

author = "Limin Wang and Wei Tang and Shouhui Yang and Peijun He and Jian Wang and Jochen Gaedcke and Philipp Str{\"o}bel and Azadeh Azizian and Thomas Ried and Gaida, \{Matthias M.\} and Yfantis, \{Harris G.\} and Lee, \{Dong H.\} and Ashish Lal and \{Van den Eynde\}, \{Benoit J.\} and Alexander, \{H. Richard\} and Ghadimi, \{B. Michael\} and Nader Hanna and Hussain, \{S. Perwez\}",

note = "Publisher Copyright: {\textcopyright} 2019 UICC",

year = "2020",

month = jun,

day = "1",

doi = "10.1002/ijc.32733",

language = "American English",

volume = "146",

pages = "3160--3169",

journal = "International Journal of Cancer",

issn = "0020-7136",

publisher = "John Wiley and Sons Inc.",

number = "11",

}

Wang, L, Tang, W, Yang, S, He, P, Wang, J, Gaedcke, J, Ströbel, P, Azizian, A, Ried, T, Gaida, MM, Yfantis, HG, Lee, DH, Lal, A, Van den Eynde, BJ, Alexander, HR, Ghadimi, BM, Hanna, N & Hussain, SP 2020, 'NO^•/RUNX3/kynurenine metabolic signaling enhances disease aggressiveness in pancreatic cancer', International Journal of Cancer, vol. 146, no. 11, pp. 3160-3169. https://doi.org/10.1002/ijc.32733

TY - JOUR

T1 - NO•/RUNX3/kynurenine metabolic signaling enhances disease aggressiveness in pancreatic cancer

AU - Wang, Limin

AU - Tang, Wei

AU - Yang, Shouhui

AU - He, Peijun

AU - Wang, Jian

AU - Gaedcke, Jochen

AU - Ströbel, Philipp

AU - Azizian, Azadeh

AU - Ried, Thomas

AU - Gaida, Matthias M.

AU - Yfantis, Harris G.

AU - Lee, Dong H.

AU - Lal, Ashish

AU - Van den Eynde, Benoit J.

AU - Alexander, H. Richard

AU - Ghadimi, B. Michael

AU - Hanna, Nader

AU - Hussain, S. Perwez

PY - 2020/6/1

Y1 - 2020/6/1

N2 - Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy and is refractory to available treatments. Delineating the regulatory mechanisms of metabolic reprogramming, a key event in pancreatic cancer progression, may identify candidate targets with potential therapeutic significance. We hypothesized that inflammatory signaling pathways regulate metabolic adaptations in pancreatic cancer. Metabolic profiling of tumors from PDAC patients with a high- (>median, n = 31) and low-NOS2 (inducible nitric oxide synthase; • (nitric oxide)-mediated signaling pathway was elucidated. The level of kynurenine, a tryptophan metabolite, was associated with high NOS2 expression, and a higher level of kynurenine predicted poor survival in patients (n = 63, p = 0.01). Gene expression analysis in PDAC tumors (n = 63) showed a positive correlation between the expression of NOS2 and the tryptophan/kynurenine pathway genes, including indoleamine-2,3-dioxygenase 1 (IDO1) and several aryl hydrocarbon receptor (AHR)-target genes including NFE2L2 (NRF2), SERPINB2, IL1b, IL6 and IL8, which are implicated in pancreatic cancer. Consistently, treatment of pancreatic cancer cell lines with NO• donor induced IDO1, kynurenine production and the expression of AHR-target genes. Furthermore, kynurenine treatment enhanced spheroid growth and invasive potential of pancreatic cancer cell lines. Mechanistically, NO•-induced IDO1/Kynurenine/AHR signaling was mediated by RUNX3 transcription factor. Our findings identified a novel NO•/RUNX3/Kynurenine metabolic axis, which enhances disease aggressiveness in pancreatic cancer and may have potential translational significance in improving disease outcome.

AB - Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy and is refractory to available treatments. Delineating the regulatory mechanisms of metabolic reprogramming, a key event in pancreatic cancer progression, may identify candidate targets with potential therapeutic significance. We hypothesized that inflammatory signaling pathways regulate metabolic adaptations in pancreatic cancer. Metabolic profiling of tumors from PDAC patients with a high- (>median, n = 31) and low-NOS2 (inducible nitric oxide synthase; • (nitric oxide)-mediated signaling pathway was elucidated. The level of kynurenine, a tryptophan metabolite, was associated with high NOS2 expression, and a higher level of kynurenine predicted poor survival in patients (n = 63, p = 0.01). Gene expression analysis in PDAC tumors (n = 63) showed a positive correlation between the expression of NOS2 and the tryptophan/kynurenine pathway genes, including indoleamine-2,3-dioxygenase 1 (IDO1) and several aryl hydrocarbon receptor (AHR)-target genes including NFE2L2 (NRF2), SERPINB2, IL1b, IL6 and IL8, which are implicated in pancreatic cancer. Consistently, treatment of pancreatic cancer cell lines with NO• donor induced IDO1, kynurenine production and the expression of AHR-target genes. Furthermore, kynurenine treatment enhanced spheroid growth and invasive potential of pancreatic cancer cell lines. Mechanistically, NO•-induced IDO1/Kynurenine/AHR signaling was mediated by RUNX3 transcription factor. Our findings identified a novel NO•/RUNX3/Kynurenine metabolic axis, which enhances disease aggressiveness in pancreatic cancer and may have potential translational significance in improving disease outcome.

KW - RUNX3

KW - kynurenine

KW - nitric oxide

KW - pancreatic cancer

KW - prognosis

KW - therapeutic targets

UR - https://www.scopus.com/pages/publications/85075365157

UR - https://www.scopus.com/pages/publications/85075365157#tab=citedBy

U2 - 10.1002/ijc.32733

DO - 10.1002/ijc.32733

M3 - Article

C2 - 31609478

SN - 0020-7136

VL - 146

SP - 3160

EP - 3169

JO - International Journal of Cancer

JF - International Journal of Cancer

IS - 11

ER -