LY294002, an inhibitor of PI-3K, enhances heat sensitivity independently of p53 status in human lung cancer cells

Abstract

The aim of this study was to ascertain whether LY294002, an inhibitor of PI-3K, enhances heat sensitivity in human cancer cells regardless of their p53 status. Colony formation assays showed that LY294002 enhanced heat sensitivity in two human lung cancer cell lines; H1299/wildtype p53 (wtp53) and H1299/mutated p53 (mp53) cells. These cell lines have identical genetic backgrounds except for their p53 status. LY294002 suppressed the heat-induced accumulation of heat shock protein 27 (hsp27) and heat shock protein 72 (hsp72) in these cell lines. Heat-induced apoptosis was observed more frequently in H1299/wtp53 cells than in H1299/mp53 cells, and was enhanced by LY294002 in both cell lines. In addition, both the heat-induced phosphorylation of Akt and the accumulation of survivin were suppressed by LY294002. These results suggest that LY294002 inhibits anti-apoptosis signaling through hsp27 and hsp72 as well as cell survival signaling through Akt and survivin. LY294002 appears to be an attractive candidate for a p53-independent heat sensitizer in hyperthermic cancer therapy.

Small molecule sensitization to TRAIL is mediated via nuclear localization, phosphorylation and inhibition of chaperone activity of Hsp27

“…20, 21, 22, 23 As LY30 is derived from LY29, we were interested to see whether artificial modulation of Hsp27 protein expression (Figure 2a) could affect the outcome of TRAIL and/or LY30 treatment. Overexpression of Hsp27 significantly rescued cells treated with LY30 and TRAIL (≥20 ng/ml) for 16 h as compared with control cells (Figures 2b and c).…”

Correlation between the expression of Id-1 and hyperthermia-associated molecules in oral squamous cell carcinoma

“…Recent studies have also shown that inhibition of the PI3K/AKT pathway can significantly increase the sensitivity of hyperthermia 14 15…”

Targeting the Protein Quality Control (PQC) Machinery

“…Inhibition of phosphatidylinositol-3-kinase (PI3-K), a known LY294002 target, causes protein kinase B (Akt) inactivation and may eventually lead to inhibition of HSF1 phosphorylation/ activation [54]. LY294002 has limited kinase specificity, and other targets may influence its cellular effects.…”

“…The benzopyranmorpholine LY294002 (2.12a) is a kinase inhibitor that down-regulates Hsp27 and Hsp70 by suppressing HSF1 binding to DNA [54]. Inhibition of phosphatidylinositol-3-kinase (PI3-K), a known LY294002 target, causes protein kinase B (Akt) inactivation and may eventually lead to inhibition of HSF1 phosphorylation/ activation [54].…”