Overexpression of PIAS3 Suppresses Cell Growth, Restores the Drug Sensitivity of Human Lung Cancer Cells in Association with PI3-K/Akt Inactivation

Constitutively activated signal transducers, activators of transcription (STAT) are reported to cause uncontrolled transmission of growth signals. In this study, we analyzed the roles of an inhibitor of STAT, protein inhibitor of activated STAT (PIAS) 3, in the development of lung cancer. Treatment with an inhibitor of phosphatidylinositol 3-kinase, LY294002, retarded the growth of human lung cancer cells, rendered them more sensitive to chemotherapeutic agents. However, the inhibition of JAK/STAT by AG490 significantly suppressed cell growth but did not increase drug sensitivity at all. Overexpression of PIAS3 not only significantly inhibited cell growth but also rendered cancer cells up to 12.0-fold more sensitive to the above drugs, which was associated with the suppression of Akt phosphorylation. Inhibition of PIAS3 with small interfering RNA, nevertheless, led cancer cells to accelerate cell proliferation, deteriorate chemosensitivity, augment Akt phosphorylation. Although the overexpression of suppressors of cytokine signaling 3 in cancer cells also inhibited cell growth, STAT3 phosphorylation, it neither increased sensitivity to chemotherapeutic drugs nor affected the phosphorylation of Akt. These results indicate that PIAS3 may be an attractive candidate for targeting the JAK/STAT, PI3-K/Akt signaling pathways in cancer treatment