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

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

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)606-612
Number of pages7
JournalInternational journal of oncology
Volume50
Issue number2
DOIs
Publication statusPublished - Feb 2017

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gemcitabine
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
1-Phosphatidylinositol 4-Kinase
Pancreatic Neoplasms
Phosphorylation
Cell Proliferation
Proto-Oncogene Proteins c-akt
Intracellular Membranes
Therapeutics
wortmannin
Cell Survival
Cell Death
Cell Line

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

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.

In: International journal of oncology, Vol. 50, No. 2, 02.2017, p. 606-612.

Research output: Contribution to journalArticle

Wang, Y, Kuramitsu, Y, Baron, B, Kitagawa, T, Tokuda, K, Akada, J, Maehara, SI, Maehara, Y & Nakamura, K 2017, 'PI3K inhibitor LY294002, as opposed to wortmannin, enhances AKT phosphorylation in gemcitabine-resistant pancreatic cancer cells', International journal of oncology, vol. 50, no. 2, pp. 606-612. https://doi.org/10.3892/ijo.2016.3804
Wang, Yufeng ; Kuramitsu, Yasuhiro ; Baron, Byron ; Kitagawa, Takao ; Tokuda, Kazuhiro ; Akada, Junko ; Maehara, Shin Ichiro ; Maehara, Yoshihiko ; Nakamura, Kazuyuki. / PI3K inhibitor LY294002, as opposed to wortmannin, enhances AKT phosphorylation in gemcitabine-resistant pancreatic cancer cells. In: International journal of oncology. 2017 ; Vol. 50, No. 2. pp. 606-612.
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