Expression signatures of the lipid-based Akt inhibitors phosphatidylinositol ether lipid analogues in NSCLC cells.

Abstract

Activation of the serine/threonine kinase Akt contributes to the formation, maintenance, and therapeutic resistance of cancer, which is driving development of compounds that inhibit Akt. Phosphatidylinositol ether lipid analogues (PIA) are analogues of the products of phosphoinositide-3-kinase (PI3K) that inhibit Akt activation, translocation, and the proliferation of a broad spectrum of cancer cell types. To gain insight into the mechanism of PIAs, time-dependent transcriptional profiling of five active PIAs and the PI3K inhibitor LY294002 (LY) was conducted in non-small cell lung carcinoma cells using high-density oligonucleotide arrays. Gene ontology analysis revealed that genes involved in apoptosis, wounding response, and angiogenesis were upregulated by PIAs, whereas genes involved in DNA replication, repair, and mitosis were suppressed. Genes that exhibited early differential expression were partitioned into three groups; those induced by PIAs only (DUSP1, KLF6, CENTD2, BHLHB2, and PREX1), those commonly induced by PIAs and LY (TRIB1, KLF2, RHOB, and CDKN1A), and those commonly suppressed by PIAs and LY (IGFBP3, PCNA, PRIM1, MCM3, and HSPA1B). Increased expression of the tumor suppressors RHOB (RhoB), KLF6 (COPEB), and CDKN1A (p21Cip1/Waf1) was validated as an Akt-independent effect that contributed to PIA-induced cytotoxicity. Despite some overlap with LY, active PIAs have a distinct expression signature that contributes to their enhanced cytotoxicity.

• Authors: Chunyu Zhang, Abdel G Elkahloun, Hongling Liao, Shannon Delaney, Barbara Saber, Betsy Morrow, George C Prendergast, M Christine Hollander, Joell J Gills, Phillip A Dennis
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 10 Issue 7 Pg. 1137-48 (Jul 2011) ISSN: 1538-8514 [Electronic] United States
• PMID: 21551261 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)
• Copyright: © 2011 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Chromones
• Enzyme Inhibitors
• Lipids
• Morpholines
• Phosphatidylinositols
• Phosphoinositide-3 Kinase Inhibitors
• 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
• Proto-Oncogene Proteins c-akt

Topics

• Antineoplastic Agents (pharmacology)
• Carcinoma, Non-Small-Cell Lung (genetics, metabolism)
• Cell Line, Tumor
• Chromones (chemistry, pharmacology)
• Cluster Analysis
• Enzyme Inhibitors (pharmacology)
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Lipids (pharmacology)
• Lung Neoplasms (genetics, metabolism)
• Morpholines (chemistry, pharmacology)
• Phosphatidylinositols (chemistry, pharmacology)
• Phosphoinositide-3 Kinase Inhibitors
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, metabolism)
• Reproducibility of Results