Overexpression of PIAS3 suppresses cell growth and restores the drug sensitivity of human lung cancer cells in association with PI3-K/Akt inactivation
Overexpression of PIAS3 suppresses cell growth and restores the drug sensitivity of human lung cancer cells in association with PI3-K/Akt inactivation
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DOI：
10.1593/neo.06409
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发表时间：
2006-10-01
期刊：
影响因子：
4.8
通讯作者：
Kawase, Ichiro
中科院分区：
文献类型：
--
作者：
Ogata, Yoshitaka;Osaki, Tadashi;Kawase, Ichiro
据报道，组成激活的信号转导器和转录激活因子（STAT）会导致生长信号的不受控制的传递。在本研究中，我们分析了STAT抑制剂，活化STAT蛋白抑制剂（PIAS） 3在肺癌发展中的作用。用磷脂酰肌醇3-激酶抑制剂LY294002治疗可以延缓人肺癌细胞的生长，并使其对化疗药物更敏感。然而，AG490对JAK/STAT的抑制作用显著抑制了细胞生长，但完全没有增加药物敏感性。PIAS3过表达不仅能显著抑制细胞生长，还能使癌细胞对上述药物的敏感性提高12.0倍，这与抑制Akt磷酸化有关。然而，用小干扰RNA抑制PIAS3会导致癌细胞加速细胞增殖，降低化学敏感性，并增加Akt磷酸化。虽然癌细胞中细胞因子信号传导3抑制因子的过度表达也会抑制细胞生长和STAT3的磷酸化，但它既不会增加对化疗药物的敏感性，也不会影响Akt的磷酸化。这些结果表明，PIAS3可能是靶向JAK/STAT和PI3-K/Akt信号通路的有吸引力的候选者。
Constitutively activated signal transducers and 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 and 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, and augment Akt phosphorylation. Although the overexpression of suppressors of cytokine signaling 3 in cancer cells also inhibited cell growth and 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 and PI3-K/Akt signaling pathways in cancer treatment.