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APE1 Promotes Pancreatic Cancer Proliferation through GFRα1/Src/ERK Axis-Cascade Signaling in Response to GDNF

Pancreatic cancer is the worst exocrine gastrointestinal cancer leading to the highest mortality. Recent studies reported that aberrant expression of apurinic/apyrimidinic endodeoxyribonuclease 1 (APE1) is involved in uncontrolled cell growth. However, the molecular mechanism of APE1 biological role...

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Autores principales: Choi, Yoo-Duk, Jung, Ji-Yeon, Baek, Minwoo, Khan, Sheema, Song, Peter I., Ryu, Sunhyo, Koo, Joo-Yeon, Chauhan, Subhash C., Tsin, Andrew, Choi, Chan, Kim, Won Jae, Kim, Mihwa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279477/
https://www.ncbi.nlm.nih.gov/pubmed/32438692
http://dx.doi.org/10.3390/ijms21103586
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author Choi, Yoo-Duk
Jung, Ji-Yeon
Baek, Minwoo
Khan, Sheema
Song, Peter I.
Ryu, Sunhyo
Koo, Joo-Yeon
Chauhan, Subhash C.
Tsin, Andrew
Choi, Chan
Kim, Won Jae
Kim, Mihwa
author_facet Choi, Yoo-Duk
Jung, Ji-Yeon
Baek, Minwoo
Khan, Sheema
Song, Peter I.
Ryu, Sunhyo
Koo, Joo-Yeon
Chauhan, Subhash C.
Tsin, Andrew
Choi, Chan
Kim, Won Jae
Kim, Mihwa
author_sort Choi, Yoo-Duk
collection PubMed
description Pancreatic cancer is the worst exocrine gastrointestinal cancer leading to the highest mortality. Recent studies reported that aberrant expression of apurinic/apyrimidinic endodeoxyribonuclease 1 (APE1) is involved in uncontrolled cell growth. However, the molecular mechanism of APE1 biological role remains unrevealed in pancreatic cancer progression. Here, we demonstrate that APE1 accelerates pancreatic cancer cell proliferation through glial cell line-derived neurotrophic factor (GDNF)/glial factor receptor α1 (GFRα1)/Src/ERK axis-cascade signaling. The proliferation of endogenous APE1 expressed-MIA PaCa-2, a human pancreatic carcinoma cell line, was increased by treatment with GDNF, a ligand of GFRα1. Either of downregulated APE1 or GFRα1 expression using small interference RNA (siRNA) inhibited GDNF-induced cancer cell proliferation. The MEK-1 inhibitor PD98059 decreased GDNF-induced MIA PaCa-2 cell proliferation. Src inactivation by either its siRNA or Src inhibitor decreased ERK-phosphorylation in response to GDNF in MIA PaCa-2 cells. Overexpression of GFRα1 in APE1-deficient MIA PaCa-2 cells activated the phosphorylation of Src and ERK. The expression of both APE1 and GFRα1 was gradually increased as progressing pancreatic cancer grades. Our results highlight a critical role for APE1 in GDNF-induced pancreatic cancer cell proliferation through APE1/GFRα1/Src/ERK axis-cascade signaling and provide evidence for future potential therapeutic drug targets for the treatment of pancreatic cancer.
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spelling pubmed-72794772020-06-17 APE1 Promotes Pancreatic Cancer Proliferation through GFRα1/Src/ERK Axis-Cascade Signaling in Response to GDNF Choi, Yoo-Duk Jung, Ji-Yeon Baek, Minwoo Khan, Sheema Song, Peter I. Ryu, Sunhyo Koo, Joo-Yeon Chauhan, Subhash C. Tsin, Andrew Choi, Chan Kim, Won Jae Kim, Mihwa Int J Mol Sci Article Pancreatic cancer is the worst exocrine gastrointestinal cancer leading to the highest mortality. Recent studies reported that aberrant expression of apurinic/apyrimidinic endodeoxyribonuclease 1 (APE1) is involved in uncontrolled cell growth. However, the molecular mechanism of APE1 biological role remains unrevealed in pancreatic cancer progression. Here, we demonstrate that APE1 accelerates pancreatic cancer cell proliferation through glial cell line-derived neurotrophic factor (GDNF)/glial factor receptor α1 (GFRα1)/Src/ERK axis-cascade signaling. The proliferation of endogenous APE1 expressed-MIA PaCa-2, a human pancreatic carcinoma cell line, was increased by treatment with GDNF, a ligand of GFRα1. Either of downregulated APE1 or GFRα1 expression using small interference RNA (siRNA) inhibited GDNF-induced cancer cell proliferation. The MEK-1 inhibitor PD98059 decreased GDNF-induced MIA PaCa-2 cell proliferation. Src inactivation by either its siRNA or Src inhibitor decreased ERK-phosphorylation in response to GDNF in MIA PaCa-2 cells. Overexpression of GFRα1 in APE1-deficient MIA PaCa-2 cells activated the phosphorylation of Src and ERK. The expression of both APE1 and GFRα1 was gradually increased as progressing pancreatic cancer grades. Our results highlight a critical role for APE1 in GDNF-induced pancreatic cancer cell proliferation through APE1/GFRα1/Src/ERK axis-cascade signaling and provide evidence for future potential therapeutic drug targets for the treatment of pancreatic cancer. MDPI 2020-05-19 /pmc/articles/PMC7279477/ /pubmed/32438692 http://dx.doi.org/10.3390/ijms21103586 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Choi, Yoo-Duk
Jung, Ji-Yeon
Baek, Minwoo
Khan, Sheema
Song, Peter I.
Ryu, Sunhyo
Koo, Joo-Yeon
Chauhan, Subhash C.
Tsin, Andrew
Choi, Chan
Kim, Won Jae
Kim, Mihwa
APE1 Promotes Pancreatic Cancer Proliferation through GFRα1/Src/ERK Axis-Cascade Signaling in Response to GDNF
title APE1 Promotes Pancreatic Cancer Proliferation through GFRα1/Src/ERK Axis-Cascade Signaling in Response to GDNF
title_full APE1 Promotes Pancreatic Cancer Proliferation through GFRα1/Src/ERK Axis-Cascade Signaling in Response to GDNF
title_fullStr APE1 Promotes Pancreatic Cancer Proliferation through GFRα1/Src/ERK Axis-Cascade Signaling in Response to GDNF
title_full_unstemmed APE1 Promotes Pancreatic Cancer Proliferation through GFRα1/Src/ERK Axis-Cascade Signaling in Response to GDNF
title_short APE1 Promotes Pancreatic Cancer Proliferation through GFRα1/Src/ERK Axis-Cascade Signaling in Response to GDNF
title_sort ape1 promotes pancreatic cancer proliferation through gfrα1/src/erk axis-cascade signaling in response to gdnf
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279477/
https://www.ncbi.nlm.nih.gov/pubmed/32438692
http://dx.doi.org/10.3390/ijms21103586
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