Over-expression of GAPDH in human colorectal carcinoma as a preferred target of 3-Bromopyruvate Propyl Ester |
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Authors: | Zhenjie Tang Shuqiang Yuan Yumin Hu Hui Zhang Wenjing Wu Zhaolei Zeng Jing Yang Jingping Yun Ruihua Xu Peng Huang |
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Institution: | State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China. |
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Abstract: | It has long been observed that many cancer cells exhibit increased aerobic glycolysis and rely more on this pathway to generate
ATP and metabolic intermediates for cell proliferation. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a key enzyme in
glycolysis and has been known as a housekeeping molecule. In the present study, we found that GAPDH expression was significantly
up-regulated in human colorectal carcinoma tissues compared to the adjacent normal tissues, and also increased in colon cancer
cell lines compared to the non-tumor colon mucosa cells in culture. The expression of GAPDH was further elevated in the liver
metastatic tissues compared to the original colon cancer tissue of the same patients, suggesting that high expression of GAPDH
might play an important role in colon cancer development and metastasis. Importantly, we found that 3-bromopyruvate propyl
ester (3-BrOP) preferentially inhibited GAPDH and exhibited potent activity in inducing colon cancer cell death by causing
severe depletion of ATP. 3-BrOP at low concentrations (1–10 μM) inhibited GAPDH and a much higher concentration (300 μM) was
required to inhibit hexokinase-2. The cytotoxic effect of 3-BrOP was associated with its inhibition of GAPDH, and colon cancer
cells with loss of p53 were more sensitive to this compound. Our study suggests that GAPDH may be a potential target for colon
cancer therapy. |
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