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...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-05-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/21/10/3586 |
| _version_ | 1797567564609486848 |
|---|---|
| author | Yoo-Duk Choi Ji-Yeon Jung Minwoo Baek Sheema Khan Peter I. Song Sunhyo Ryu Joo-Yeon Koo Subhash C. Chauhan Andrew Tsin Chan Choi Won Jae Kim Mihwa Kim |
| author_facet | Yoo-Duk Choi Ji-Yeon Jung Minwoo Baek Sheema Khan Peter I. Song Sunhyo Ryu Joo-Yeon Koo Subhash C. Chauhan Andrew Tsin Chan Choi Won Jae Kim Mihwa Kim |
| author_sort | Yoo-Duk Choi |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-10T19:43:46Z |
| format | Article |
| id | doaj.art-60efd41876964aea905d400aa63baada |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T19:43:46Z |
| publishDate | 2020-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-60efd41876964aea905d400aa63baada2023-11-20T00:58:56ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-05-012110358610.3390/ijms21103586APE1 Promotes Pancreatic Cancer Proliferation through GFRα1/Src/ERK Axis-Cascade Signaling in Response to GDNFYoo-Duk Choi0Ji-Yeon Jung1Minwoo Baek2Sheema Khan3Peter I. Song4Sunhyo Ryu5Joo-Yeon Koo6Subhash C. Chauhan7Andrew Tsin8Chan Choi9Won Jae Kim10Mihwa Kim11Department of Pathology, Chonnam National University Medical School, Gwangju 61186, KoreaDental Science Research Institute, Medical Research Center for Biomineralization Disorders, School of Dentistry, Chonnam National University, Gwangju 61186, KoreaDepartment of Pharmacy Practice and Pharmaceutical Sciences, College of Pharmacy, University of Minnesota, Duluth, MN 55812, USADepartment of Immunology & Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USADepartment of Molecular Science, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USADivision of Pulmonary and Critical Care Medicine, Department of Medicine, Boston University Medical Campus, Boston, MA 02118, USADepartment of Pathology, Chonnam National University Medical School, Gwangju 61186, KoreaDepartment of Immunology & Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USADepartment of Molecular Science, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USADepartment of Pathology, Chonnam National University Hwasun Hospital, Hwasun 58128, KoreaDental Science Research Institute, Medical Research Center for Biomineralization Disorders, School of Dentistry, Chonnam National University, Gwangju 61186, KoreaDepartment of Pathology, Chonnam National University Medical School, Gwangju 61186, KoreaPancreatic 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.https://www.mdpi.com/1422-0067/21/10/3586APE1GFRα1Src/ERKpancreatic cancerproliferation |
| spellingShingle | Yoo-Duk Choi Ji-Yeon Jung Minwoo Baek Sheema Khan Peter I. Song Sunhyo Ryu Joo-Yeon Koo Subhash C. Chauhan Andrew Tsin Chan Choi Won Jae Kim Mihwa Kim APE1 Promotes Pancreatic Cancer Proliferation through GFRα1/Src/ERK Axis-Cascade Signaling in Response to GDNF International Journal of Molecular Sciences APE1 GFRα1 Src/ERK pancreatic cancer proliferation |
| 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 | APE1 GFRα1 Src/ERK pancreatic cancer proliferation |
| url | https://www.mdpi.com/1422-0067/21/10/3586 |
| work_keys_str_mv | AT yoodukchoi ape1promotespancreaticcancerproliferationthroughgfra1srcerkaxiscascadesignalinginresponsetogdnf AT jiyeonjung ape1promotespancreaticcancerproliferationthroughgfra1srcerkaxiscascadesignalinginresponsetogdnf AT minwoobaek ape1promotespancreaticcancerproliferationthroughgfra1srcerkaxiscascadesignalinginresponsetogdnf AT sheemakhan ape1promotespancreaticcancerproliferationthroughgfra1srcerkaxiscascadesignalinginresponsetogdnf AT peterisong ape1promotespancreaticcancerproliferationthroughgfra1srcerkaxiscascadesignalinginresponsetogdnf AT sunhyoryu ape1promotespancreaticcancerproliferationthroughgfra1srcerkaxiscascadesignalinginresponsetogdnf AT jooyeonkoo ape1promotespancreaticcancerproliferationthroughgfra1srcerkaxiscascadesignalinginresponsetogdnf AT subhashcchauhan ape1promotespancreaticcancerproliferationthroughgfra1srcerkaxiscascadesignalinginresponsetogdnf AT andrewtsin ape1promotespancreaticcancerproliferationthroughgfra1srcerkaxiscascadesignalinginresponsetogdnf AT chanchoi ape1promotespancreaticcancerproliferationthroughgfra1srcerkaxiscascadesignalinginresponsetogdnf AT wonjaekim ape1promotespancreaticcancerproliferationthroughgfra1srcerkaxiscascadesignalinginresponsetogdnf AT mihwakim ape1promotespancreaticcancerproliferationthroughgfra1srcerkaxiscascadesignalinginresponsetogdnf |