PI3K inhibitor LY294002, as opposed to wortmannin, enhances AKT phosphorylation in gemcitabine-resistant pancreatic cancer cells

Wang,Yufeng; Kuramitsu,Yasuhiro; Baron,Byron; Kitagawa,Takao; Tokuda,Kazuhiro; Akada,Junko; Maehara,Shin-Ichiro; Maehara,Yoshihiko; Nakamura,Kazuyuki

doi:10.3892/ijo.2016.3804

PI3K inhibitor LY294002, as opposed to wortmannin, enhances AKT phosphorylation in gemcitabine-resistant pancreatic cancer cells

Authors:
- Yufeng Wang
- Yasuhiro Kuramitsu
- Byron Baron
- Takao Kitagawa
- Kazuhiro Tokuda
- Junko Akada
- Shin-Ichiro Maehara
- Yoshihiko Maehara
- Kazuyuki Nakamura
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Affiliations: Department of Biochemistry and Functional Proteomics, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan, Department of Surgery and Science, Graduate School of Medical Science, Kyusyu University, Fukuoka, Japan, Centre for Molecular Medicine and Biobanking, University of Malta, Msida, Republic of Malta
Published online on: December 14, 2016 https://doi.org/10.3892/ijo.2016.3804
Pages: 606-612

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Abstract

LY294002 and wortmannin are chemical compounds that act as potent inhibitors of phosphoinositide 3-kinases (PI3Ks). Both of them are generally used to inhibit cell proliferation as cancer treatment by inhibiting the PI3K/protein kinase B (AKT) signaling pathway. In this study, LY294002 (but not wortmannin) showed an abnormal ability to enhance AKT phosphorylation (at Ser472) specifically in gemcitabine (GEM)-resistant pancreatic cancer (PC) cell lines PK59 and KLM1-R. LY294002 was shown to activate AKT and accumulate phospho-AKT at the intracellular membrane in PK59, which was abolished by treatment with AKTi-1/2 or wortmannin. Inhibiting AKT phosphorylation by treatment with AKTi-1/2 or wortmannin further enhanced LY294002-induced cell death in PK59 and KLM1-R cells. In addition, treatment with wortmannin alone failed to inhibit cell proliferation in both PK59 and KLM1-R cells. Thus, our results reveal that LY294002 displays the opposite effect on PI3K-dependent AKT phosphorylation, which maintains cell survival from the cytotoxicity introduced by LY294002 itself in GEM-resistant pancreatic cancer cells. We suggest that targeting the PI3K/AKT signaling pathway with inhibitors may be counterproductive for patients with PC who have acquired GEM-resistance.

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