The therapeutic targeting of the FGFR1/Src/NF-κB signaling axis inhibits pancreatic ductal adenocarcinoma stemness and oncogenicity

Shiue Wei Lai, Oluwaseun Adebayo Bamodu, Wen Chiuan Tsai, Yi Ming Chang, Wei Hwa Lee, Chi Tai Yeh, Tsu Yi Chao

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

The aberrant activation of the FGFR signaling is detected in many solid tumors, including pancreatic ductal adenocarcinoma (PDAC), suggesting it as a potential therapeutic target. In this study, we investigated the antitumor and anti-metastasis efficacy of the selective FGFR1 inhibitor, PD173074 in PDAC. We used immunohistochemical and in situ hybridization analyses to demonstrate a strong correlation between FGFR1 amplification and/or expression and disease progression in PDAC patients. We showed that ALDHhigh (ALDH+) pancreatic cancer cells exhibited stem cell-like phenotype and expressed higher levels of FGFR1, Src, NF-κB, alongside stemness markers like Oct4 and Sox2, compared to their ALDHlow/null (ALDH−) counterparts, suggesting the preferential activation of the FGFR1/Src/NF-κB signaling axis in pancreatic cancer stem cells (panCSCs). Furthermore, treatment of the ALDHhigh/ FGFR1-rich pancreatic cancer cell lines with PD173074, a selective FGFR1 inhibitor, revealed that PD173074 inhibited the proliferation and self-renewal of the panCSCs, and induced their apoptosis by activating caspase-3 and cleaving Poly-ADP ribose Polymerase (PARP). The anti-CSCs effect of PD173074 was associated with decreased expression of Oct4, Sox-2, Nanog, and c-Myc, as well as suppression of XIAP, Bcl2, and survivin expression, dose-dependently. Additionally, activation of cMet, Src, ERK 1/2 and NFκB (p65) was also inhibited by PD173074. Also, of clinical relevance, the disruption of the FGFR1/Src/NF-κB signaling axis positively correlated with poor clinical prognosis among the PDAC patients. We concluded that PD173074 suppresses the tumorigenesis and CSCs-like phenotype of PDAC cells, highlighting its therapeutic efficacy and providing support for its potential use as a therapeutic option for the ‘difficult-to-treat’, ‘quick-to-relapse’ PDAC patients. Graphical Abstract: Schematic abstract showing how PD173074 inhibits PDAC growth through selective targeting of FGFR1, suppression of cancer stemness, disruption of the FGFR1/Src/NF-κB signaling axis and activation of the cell death signaling pathway. [Figure not available: see fulltext.]

Original languageEnglish
Pages (from-to)1-15
Number of pages15
JournalClinical and Experimental Metastasis
DOIs
Publication statusAccepted/In press - Jul 9 2018

Fingerprint

Adenocarcinoma
Pancreatic Neoplasms
Neoplastic Stem Cells
Therapeutics
Phenotype
Poly(ADP-ribose) Polymerases
PD 173074
Caspase 3
In Situ Hybridization
Disease Progression
Neoplasms
Carcinogenesis
Cell Death
Stem Cells
Apoptosis
Neoplasm Metastasis
Recurrence
Cell Line
Growth

Keywords

  • ALDH
  • Cancer stem cells
  • FGFR1
  • FGFR1/Src/NF-κB signaling
  • Pancreatic cancer
  • PD173074
  • Selective inhibitor

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

@article{41742aaee0f8474e8aa7bd3b700b16ce,
title = "The therapeutic targeting of the FGFR1/Src/NF-κB signaling axis inhibits pancreatic ductal adenocarcinoma stemness and oncogenicity",
abstract = "The aberrant activation of the FGFR signaling is detected in many solid tumors, including pancreatic ductal adenocarcinoma (PDAC), suggesting it as a potential therapeutic target. In this study, we investigated the antitumor and anti-metastasis efficacy of the selective FGFR1 inhibitor, PD173074 in PDAC. We used immunohistochemical and in situ hybridization analyses to demonstrate a strong correlation between FGFR1 amplification and/or expression and disease progression in PDAC patients. We showed that ALDHhigh (ALDH+) pancreatic cancer cells exhibited stem cell-like phenotype and expressed higher levels of FGFR1, Src, NF-κB, alongside stemness markers like Oct4 and Sox2, compared to their ALDHlow/null (ALDH−) counterparts, suggesting the preferential activation of the FGFR1/Src/NF-κB signaling axis in pancreatic cancer stem cells (panCSCs). Furthermore, treatment of the ALDHhigh/ FGFR1-rich pancreatic cancer cell lines with PD173074, a selective FGFR1 inhibitor, revealed that PD173074 inhibited the proliferation and self-renewal of the panCSCs, and induced their apoptosis by activating caspase-3 and cleaving Poly-ADP ribose Polymerase (PARP). The anti-CSCs effect of PD173074 was associated with decreased expression of Oct4, Sox-2, Nanog, and c-Myc, as well as suppression of XIAP, Bcl2, and survivin expression, dose-dependently. Additionally, activation of cMet, Src, ERK 1/2 and NFκB (p65) was also inhibited by PD173074. Also, of clinical relevance, the disruption of the FGFR1/Src/NF-κB signaling axis positively correlated with poor clinical prognosis among the PDAC patients. We concluded that PD173074 suppresses the tumorigenesis and CSCs-like phenotype of PDAC cells, highlighting its therapeutic efficacy and providing support for its potential use as a therapeutic option for the ‘difficult-to-treat’, ‘quick-to-relapse’ PDAC patients. Graphical Abstract: Schematic abstract showing how PD173074 inhibits PDAC growth through selective targeting of FGFR1, suppression of cancer stemness, disruption of the FGFR1/Src/NF-κB signaling axis and activation of the cell death signaling pathway. [Figure not available: see fulltext.]",
keywords = "ALDH, Cancer stem cells, FGFR1, FGFR1/Src/NF-κB signaling, Pancreatic cancer, PD173074, Selective inhibitor",
author = "Lai, {Shiue Wei} and Bamodu, {Oluwaseun Adebayo} and Tsai, {Wen Chiuan} and Chang, {Yi Ming} and Lee, {Wei Hwa} and Yeh, {Chi Tai} and Chao, {Tsu Yi}",
year = "2018",
month = "7",
day = "9",
doi = "10.1007/s10585-018-9919-5",
language = "English",
pages = "1--15",
journal = "Clinical and Experimental Metastasis",
issn = "0262-0898",
publisher = "Springer Netherlands",

}

TY - JOUR

T1 - The therapeutic targeting of the FGFR1/Src/NF-κB signaling axis inhibits pancreatic ductal adenocarcinoma stemness and oncogenicity

AU - Lai, Shiue Wei

AU - Bamodu, Oluwaseun Adebayo

AU - Tsai, Wen Chiuan

AU - Chang, Yi Ming

AU - Lee, Wei Hwa

AU - Yeh, Chi Tai

AU - Chao, Tsu Yi

PY - 2018/7/9

Y1 - 2018/7/9

N2 - The aberrant activation of the FGFR signaling is detected in many solid tumors, including pancreatic ductal adenocarcinoma (PDAC), suggesting it as a potential therapeutic target. In this study, we investigated the antitumor and anti-metastasis efficacy of the selective FGFR1 inhibitor, PD173074 in PDAC. We used immunohistochemical and in situ hybridization analyses to demonstrate a strong correlation between FGFR1 amplification and/or expression and disease progression in PDAC patients. We showed that ALDHhigh (ALDH+) pancreatic cancer cells exhibited stem cell-like phenotype and expressed higher levels of FGFR1, Src, NF-κB, alongside stemness markers like Oct4 and Sox2, compared to their ALDHlow/null (ALDH−) counterparts, suggesting the preferential activation of the FGFR1/Src/NF-κB signaling axis in pancreatic cancer stem cells (panCSCs). Furthermore, treatment of the ALDHhigh/ FGFR1-rich pancreatic cancer cell lines with PD173074, a selective FGFR1 inhibitor, revealed that PD173074 inhibited the proliferation and self-renewal of the panCSCs, and induced their apoptosis by activating caspase-3 and cleaving Poly-ADP ribose Polymerase (PARP). The anti-CSCs effect of PD173074 was associated with decreased expression of Oct4, Sox-2, Nanog, and c-Myc, as well as suppression of XIAP, Bcl2, and survivin expression, dose-dependently. Additionally, activation of cMet, Src, ERK 1/2 and NFκB (p65) was also inhibited by PD173074. Also, of clinical relevance, the disruption of the FGFR1/Src/NF-κB signaling axis positively correlated with poor clinical prognosis among the PDAC patients. We concluded that PD173074 suppresses the tumorigenesis and CSCs-like phenotype of PDAC cells, highlighting its therapeutic efficacy and providing support for its potential use as a therapeutic option for the ‘difficult-to-treat’, ‘quick-to-relapse’ PDAC patients. Graphical Abstract: Schematic abstract showing how PD173074 inhibits PDAC growth through selective targeting of FGFR1, suppression of cancer stemness, disruption of the FGFR1/Src/NF-κB signaling axis and activation of the cell death signaling pathway. [Figure not available: see fulltext.]

AB - The aberrant activation of the FGFR signaling is detected in many solid tumors, including pancreatic ductal adenocarcinoma (PDAC), suggesting it as a potential therapeutic target. In this study, we investigated the antitumor and anti-metastasis efficacy of the selective FGFR1 inhibitor, PD173074 in PDAC. We used immunohistochemical and in situ hybridization analyses to demonstrate a strong correlation between FGFR1 amplification and/or expression and disease progression in PDAC patients. We showed that ALDHhigh (ALDH+) pancreatic cancer cells exhibited stem cell-like phenotype and expressed higher levels of FGFR1, Src, NF-κB, alongside stemness markers like Oct4 and Sox2, compared to their ALDHlow/null (ALDH−) counterparts, suggesting the preferential activation of the FGFR1/Src/NF-κB signaling axis in pancreatic cancer stem cells (panCSCs). Furthermore, treatment of the ALDHhigh/ FGFR1-rich pancreatic cancer cell lines with PD173074, a selective FGFR1 inhibitor, revealed that PD173074 inhibited the proliferation and self-renewal of the panCSCs, and induced their apoptosis by activating caspase-3 and cleaving Poly-ADP ribose Polymerase (PARP). The anti-CSCs effect of PD173074 was associated with decreased expression of Oct4, Sox-2, Nanog, and c-Myc, as well as suppression of XIAP, Bcl2, and survivin expression, dose-dependently. Additionally, activation of cMet, Src, ERK 1/2 and NFκB (p65) was also inhibited by PD173074. Also, of clinical relevance, the disruption of the FGFR1/Src/NF-κB signaling axis positively correlated with poor clinical prognosis among the PDAC patients. We concluded that PD173074 suppresses the tumorigenesis and CSCs-like phenotype of PDAC cells, highlighting its therapeutic efficacy and providing support for its potential use as a therapeutic option for the ‘difficult-to-treat’, ‘quick-to-relapse’ PDAC patients. Graphical Abstract: Schematic abstract showing how PD173074 inhibits PDAC growth through selective targeting of FGFR1, suppression of cancer stemness, disruption of the FGFR1/Src/NF-κB signaling axis and activation of the cell death signaling pathway. [Figure not available: see fulltext.]

KW - ALDH

KW - Cancer stem cells

KW - FGFR1

KW - FGFR1/Src/NF-κB signaling

KW - Pancreatic cancer

KW - PD173074

KW - Selective inhibitor

UR - http://www.scopus.com/inward/record.url?scp=85049613111&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85049613111&partnerID=8YFLogxK

U2 - 10.1007/s10585-018-9919-5

DO - 10.1007/s10585-018-9919-5

M3 - Article

AN - SCOPUS:85049613111

SP - 1

EP - 15

JO - Clinical and Experimental Metastasis

JF - Clinical and Experimental Metastasis

SN - 0262-0898

ER -