A Study On The Expression Of CIP2A And Its Inhibitors' Anti-cancer Efficacy In Lung Cancer

Lung cancer is the leading cause of cancer deaths worldwide. Each year nearly 1.5 million people are diagnosed with lung cancer, accounting for about 12% of total cancer diagnosed. Lung cacner has become the major human health risk. Although there are some improvements in lung caner therapies, the disease can hardly be cured and the prognosis is poor, with the five-year survival rate for all stages combined is only 15%, highlighting the urgent need for identifation of novel molecular targets for lung cancer chemotherapy.Cancerous inhibitor of phosphatase PP2A (CIP2A) was an auto-antigen that first identified in hepatocarcinoma, and later research showed that CIP2A could stabilize c-Myc by inhibiting protein phosphatase 2A (PP2A)-mediated dephosphorylation of c-Myc, and is required for cell proliferation and transformation. However, to date, the function of CIP2A and related signaling pathways remain obscure. Furthermore, the expression of CIP2A and its roles in lung cancer is unclear, and whether CIP2A can serve as a new drug target for lung cancer or not need to be determined. In addition, lead compounds that can modulate CIP2A expression for the lung cancer therapy warrant further investigation. This paper will address the above questions in detail.Firstly, western blotting was conducted to evaluate the expression of CIP2A in lung cancer cells and normal human embryonic lung fibroblast and human bronchial epithelial cells, and the result showed that CIP2A at protein level was highly expressed in lung cancer cells compared with lung-derived normal cells. This finding was accordance with the results from lung tumor samples detected by western blotting, immunohistochemistry and reverse transcription-PCR methods, which reported that, at mRNA and protein levels, CIP2A was undetectable or very low in paratumor tissues, but was dramatically elevated in tumor samples in 38 (63.3%) out of 60 patients. Multivariate logistic regression analysis demonstrated that cigarette smoking was the only significant variable associated with CIP2A overexpression in lung cancer. Silencing CIP2A by siRNA inhibited the proliferation and clonogenic activity of lung cancer cells. Basing on these results, we tried to indentify natural compounds that could modulate CIP2A expression, and found a natural compound, rabdocoetsin B, which was extracted from a Traditional Chinese Medicinal herb Rabdosia coetsa, could induce the down-regulation of CIP2A protein by suppressing its transcription, and inhibit CIP2A-Akt pathway. Furthermore, rabdocoetsin B had the ability to inhibit proliferation and induce apoptosis in a variety of lung cancer cells. Intriguingly, another compound extracted from a Traditional Chinese Medicinal herb, LTZ010, was also identified and shown to have the ability to trigger a rapid turnover of CIP2A through ubiquitin-proteasome pathway. Besides, LTZ010 exhibited significantly antitumor activity both in vitro and in vivo.Our findings suggest that CIP2A will be a promising target for lung cancer therapy and two natural compounds, rabdocoetsin B and LTZ010 that can induce downregulation of CIP2A, exhibit great potential for lung cancer chemotherapy.