ZSTK474, a specific class I phosphatidylinositol 3-kinase inhibitor, induces G1 arrest and autophagy in human breast cancer MCF-7 cells.

Abstract

Multifaceted activities of class I phosphatidylinositol 3-kinase (PI3K) inhibitor ZSTK474 were investigated on human breast cancer cell MCF-7. ZSTK474 inhibited proliferation of MCF-7 cells potently. Flow cytometric analysis indicated that ZSTK474 induced cell cycle arrest at G1 phase, but no obvious apoptosis occurred. Western blot analysis suggested that blockade of PI3K/Akt/GSK-3β/cyclin D1/p-Rb pathway might contribute to the G1 arrest induced. Moreover, we demonstrated that ZSTK474 induced autophagy in MCF-7 cells by use of various assays including monodansylcadaverine (MDC) staining, transmission electron microscopy (TEM), tandem mRFP-GFP-LC3 fluorescence microscopy, and western blot detection of the autophagy protein markers of LC3B II, p62 and Atg 5. Inhibition of class I PI3K and the downstream mTOR might be involved in the autophagy-inducing effect. Combinational use of ZSTK474 and autophagy inhibitors enhanced cell viability, suggesting ZSTK474-induced autophagy might contribute to the antitumor activity. Our report supports the application of ZSTK474, which is being evaluated in clinical trials, for breast cancer therapy.

• Authors: Yaochen Wang, Jing Liu, Yuling Qiu, Meihua Jin, Xi Chen, Guanwei Fan, Ran Wang, Dexin Kong
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 15 Pg. 19897-909 (Apr 12 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 26918351 (Publication Type: Journal Article)

Chemical References

• Triazines
• ZSTK474
• Cyclin D1
• MTOR protein, human
• Class I Phosphatidylinositol 3-Kinases
• Glycogen Synthase Kinase 3 beta
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases

Topics

• Autophagy (drug effects)
• Blotting, Western
• Breast Neoplasms (metabolism, pathology, ultrastructure)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Class I Phosphatidylinositol 3-Kinases (antagonists & inhibitors, metabolism)
• Cyclin D1 (metabolism)
• G1 Phase Cell Cycle Checkpoints (drug effects)
• Glycogen Synthase Kinase 3 beta (metabolism)
• Humans
• MCF-7 Cells
• Microscopy, Electron, Transmission
• Microscopy, Fluorescence
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction (drug effects)
• TOR Serine-Threonine Kinases (metabolism)
• Triazines (pharmacology)