Simultaneous blockade of AP-1 and phosphatidylinositol 3-kinase pathway in non-small cell lung cancer cells

Abstract

c-Jun is a major constituent of AP-1 transcription factor that transduces multiple mitogen growth signals, and it is frequently overexpressed in non-small cell lung cancers (NSCLCs). Earlier, we showed that blocking AP-1 by the overexpression of a c-Jun dominant-negative mutant, TAM67, inhibited NSCLC cell growth. The phosphatidylinositol 3-kinase (PI3K)/Akt signal transduction pathway is important in transformation, proliferation, survival and metastasis of NSCLC cells. In this study, we used NCI-H1299 Tet-on clone cells that express TAM67 under the control of inducible promoter to determine the effects of inhibition of AP-1 and PI3K on cell growth. The PI3K inhibitor, LY294002, produced a dose-dependent inhibition of growth in H1299 cells and that inhibition was enhanced by TAM67. TAM67 increased dephosphorylation of Akt induced by LY294002 and reduced the TPA response element DNA-binding of phosphorylated c-Jun. TAM67 increased G1 cell cycle blockade induced by LY294002, which was partially associated with cyclin A decrease and p27 Kip1 accumulation. Furthermore, TAM67 and LY294002 act, at least additively, to inhibit anchorage-independent growth of the H1299 cells. These results suggest that AP-1 and PI3K/Akt pathways play an essential role in the growth of some NSCLC cells.

Minichromosome maintenance (MCM) protein 4 as a marker for proliferation and its clinical and clinicopathological significance in non-small cell lung cancer

“…We have previously shown that blocking AP-1 transcription factor by TAM67 inhibited the growth of NSCLC cells [3,4]. We confirmed that the induction of TAM67 decreased expression of MCM4 and inhibition of MCM4 expression by siRNA reduced cell proliferation in H1299 cell, thus suggesting that TAM67 inhibits cell proliferation partially due to reduced expression of MCM4 in H1299 cells.…”

“…1A, [3,4]). To identify downstream effectors relevant to the growth inhibition, we performed microarray analysis.…”

“…We have previously shown that blocking AP-1 transcription factor by a cJun dominant-negative mutant, TAM67, inhibited growth of non-small cell lung cancer (NSCLC) cells including NCI-H1299 (H1299) cells [3,4]. To identify effectors relevant to the growth inhibition, we performed microarray analysis and found that TAM67 decreased mRNA levels of minichromosome maintenance (MCM) protein 4 in H1299 cells.…”

Identification of genes involved in radioresistance of nasopharyngeal carcinoma by integrating gene ontology and protein-protein interaction networks

“…JUN is a proto-oncogene, expression of c-Jun promotes cellular survival by negatively regulating the expression of the tumor-suppressor PTEN (35). c-Jun is a major constituent of AP-1 transcription factor that transduces multiple mitogen growth signals (36). Expression of AP-1 proteins has been associated with a more aggressive clinical outcome in prostate cancer.…”

Carcinogenic risk of chromium, copper and arsenic in CCA-treated wood

“…Thus, our experimental research further revealed the molecular mechanism for the synergistic increase of transforming activity by coexposure to Cr and As. Since the PI3K/AKT signaling pathway has been reported to be involved in the transformation of various cancers including lung carcinoma (Kikuchi et al, 2008;Patek et al, 2008;Molina-Arcas et al, 2013;Thang et al, 2015), synergistic activation of the PI3K/AKT signaling pathway by co-exposure to Cr and As may be involved in the increased transforming activity of BEAS-2B human lung epithelial cells.…”