The Role of Pyruvate Kinase M2 in Growth, Invasion and Drug Resistance in Human Urothelial Carcinoma

Bladder Urothelial Carcinoma

Bladder urothelial carcinoma (UC), pyruvate kinase, drug resistance, shikonin

Bladder urothelial carcinoma (UC) is a common malignancy and the incidence is increasing by years in Taiwan. Chemoresistance was inevitable in treatment of metastatic disease and lead to the ominous outcomes. To develop novel therapeutic strategies to overcome chemoresistance is imperative. Cancer cells uptake glucose at higher rates than normal tissue but use most of glucose for glycolysis even under normoxia condition, which is known as the Warburg effect. Pyruvate kinase (PK) catalyzes the last step in the process of glycolysis, and one of it isoform--PKM2 has been reported to be associated with tumor progression and some specific tissues and promotes the Warburg effect in cancer cells.

Regulation of PKM2 can be a novel target of cancer therapy. Meanwhile, PKM2 may play a critical role in the development of drug resistance and can be a promising target to overcome drug resistance. In this study, our specific aims are as follows: 1. To prove the differentia expression levels of PKM2 in UC cells and drug-resistant UC cells, as well as in human UC tissues and drug-resistant UC tissues. 2. To examine the effect of PKM2 regulations（PKM2 siRNA and shikonin）on invasiveness and metastatic ability of UC cells and clarify the role of PKM2 in human UC cells. 3. To investigate the combinatory effect of PKM2 regulations（PKM2 siRNA and shikonin）and currently used chemotherapeutic agents (cisplatin，gemcitabine ,doxorubicin). Do PKM2 regulations enhance the cytotoxic effect of chemotherapy and overcome the chemoresistance？ 4. To further prove the in vitro findings in the nude mice xenograft model。

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