A novel PP2A enhancer induces caspase-independent apoptosis of MKN28 gastric cancer cells with high MEK activity

• Published in: Cancer letters Vol. 347; no. 1; pp. 123 - 128
• Main Authors: Tsuchiya, Ayako, Kanno, Takeshi, Shimizu, Tadashi, Nakao, Syuhei, Tanaka, Akito, Tabata, Chiharu, Nakano, Takashi, Nishizaki, Tomoyuki
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 28-05-2014; Elsevier Limited
• Subjects: Apoptosis; Aqueous solutions; Cancer cell; Caspase-independent apoptosis; Caspases - metabolism; Cell growth; Cell Line, Tumor; Gastric cancer; Hematology, Oncology and Palliative Medicine; Humans; In Situ Nick-End Labeling; Kidney cancer; Kinases; MAP Kinase Kinase Kinases - metabolism; MEK; Phosphatase; Phosphatidylinositol derivative; Phosphorylation; Protein Phosphatase 2 - metabolism; Protein phosphatase 2A; Proteins; Stomach Neoplasms - enzymology; Stomach Neoplasms - pathology; Cancer cell; MEK; Phosphatidylinositol derivative; Caspase-independent apoptosis; Protein phosphatase 2A
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2014.01.034

Abstract The newly synthesized phosphatidylinositol (PI) derivative 1,2- O -bis-[8-{2-(2-pentyl-cyclopropylmethyl)-cyclopropyl}-octanoyl]- sn -glycero-3-phosphatidyl- D -1-inositol (diDCP-LA-PI) significantly enhanced protein phosphatase 2A (PP2A) activity in the cell-free assay. This prompted to assess the antitumor effect of diDCP-LA-PI. diDCP-LA-PI attenuated phosphorylation of mitogen-activated protein kinase (MAPK) kinase (MEK) in Lu65 human lung cancer and MKN28 human gastric cancer cells with high MEK activity. diDCP-LA-PI reduced cell viability in Lu65 and MKN28 cells, but otherwise such effect was not found in 786-O human renal cancer and HUH-7 human hepatoma cells with relatively low MEK activity. For Lu65 and MKN28 cells diDCP-LA-PI increased terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells, but no significant activation of caspase-3, -8, or -9 was obtained. For MKN28 cells diDCP-LA-PI-induced reduction of MEK phosphorylation and cell viability was prevented by knocking-down PP2Ac. Taken together, these results indicate that diDCP-LA-PI induces caspase-independent apoptosis of Lu65 and MKN28 human cancer cells, for the latter cells by suppressing MEK activity through PP2A-catalyzed dephosphorylation.