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

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.

• Authors: Yufeng Wang, Yasuhiro Kuramitsu, Byron Baron, Takao Kitagawa, Kazuhiro Tokuda, Junko Akada, Shin-Ichiro Maehara, Yoshihiko Maehara, Kazuyuki Nakamura
• Journal: International journal of oncology (Int J Oncol) Vol. 50 Issue 2 Pg. 606-612 (Feb 2017) ISSN: 1791-2423 [Electronic] Greece
• PMID: 28000865 (Publication Type: Journal Article)

Chemical References

• Androstadienes
• Chromones
• Morpholines
• Deoxycytidine
• 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
• Proto-Oncogene Proteins c-akt
• Wortmannin
• Gemcitabine

Topics

• Androstadienes (pharmacology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Chromones (pharmacology)
• Deoxycytidine (analogs & derivatives, pharmacology)
• Drug Resistance, Neoplasm (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Morpholines (pharmacology)
• Pancreatic Neoplasms (drug therapy, metabolism)
• Phosphorylation (drug effects)
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction (drug effects)
• Wortmannin
• Gemcitabine