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

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17 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

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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    Wang, Y., Kuramitsu, Y., Baron, B., Kitagawa, T., Tokuda, K., Akada, J., Maehara, S. I., 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, 50(2), 606-612. https://doi.org/10.3892/ijo.2016.3804