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

Yoo-Duk Choi,Won Jae Kim,Minwoo Baek,Subhash C Chauhan,Ji-Yeon Jung,Peter I Song,Andrew Tsin,Sunhyo Ryu,Mihwa Kim,Sheema Khan,Chan Choi,Joo-Yeon Koo

doi:10.3390/ijms21103586

Abstract

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.

Highlights

The multifunctional protein apurinic/apyrimidinic endonuclease (APE1) consists of a DNA repair domain at the C-terminus and a redox regulation domain at the N-terminus
We examined whether apyrimidinic endodeoxyribonuclease 1 (APE1)-mediated regulation of glial factor receptor α1 (GFRα1) expression has effects on pancreatic cancer cell proliferation using pancreatic cancer cells and human patient tissues, and its mechanism
MIA PaCa-2 human pancreatic cancer cells, which contain endogenous APE1, were treated with glial cell line-derived neurotrophic factor (GDNF), a binding partner of GFRα1 to investigate the effect of GDNF on pancreatic cancer cell proliferation (Figure 1a)

Summary

Introduction

The multifunctional protein apurinic/apyrimidinic endonuclease (APE1) consists of a DNA repair domain at the C-terminus and a redox regulation domain at the N-terminus. The latter functions in the regulation of transcription factors that are involved in cancer promotion and progression such as AP-1, NF-κB, p53, Egr-1, c-Myb, HLF, Pax-8, and STAT3 [1,2,3,4,5]. A lack of early detection screening methods for the disease and its resistance to radiation and chemotherapy contribute to a median 5 year overall survival rate of less than 4% and annual mortality figures that equal the annual rates of incidence in the United States [17]

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