Ho Nelson, Morrison Jodi, Silva Andreza, Coomber Brenda L
Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada, N1G 2W1.
Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada, N1G 2W1
Biosci Rep. 2016 Jan 6;36(1):e00299. doi: 10.1042/BSR20150267.
Cancer cells heavily rely on the glycolytic pathway regardless of oxygen tension. Hexokinase II (HKII) catalyses the first irreversible step of glycolysis and is often overexpressed in cancer cells. 3-Bromopyruvate (3BP) has been shown to primarily target HKII, and is a promising anti-cancer compound capable of altering critical metabolic pathways in cancer cells. Abnormal vasculature within tumours leads to heterogeneous microenvironments, including glucose availability, which may affect drug sensitivity. The aim of the present study was to elucidate the mechanisms by which 3BP acts on colorectal cancer (CRC) cells with focus on the HKII/Akt signalling axis. High HKII-expressing cell lines were more sensitive to 3BP than low HKII-expressing cells. 3BP-induced rapid Akt phosphorylation at site Thr-308 and cell death via both apoptotic and necrotic mechanisms. Cells grown under lower glucose concentrations showed greater resistance towards 3BP. Cells with HKII knockdown showed no changes in 3BP sensitivity, suggesting the effects of 3BP are independent of HKII expression. These results emphasize the importance of the tumour microenvironment and glucose availability when considering therapeutic approaches involving metabolic modulation.
癌细胞无论氧张力如何，都严重依赖糖酵解途径。己糖激酶II（HKII）催化糖酵解的第一步不可逆反应，且在癌细胞中常过度表达。3-溴丙酮酸（3BP）已被证明主要作用于HKII，是一种有前景的抗癌化合物，能够改变癌细胞中的关键代谢途径。肿瘤内的异常血管会导致异质性微环境，包括葡萄糖的可利用性，这可能会影响药物敏感性。本研究的目的是阐明3BP作用于结肠直肠癌（CRC）细胞的机制，重点关注HKII/Akt信号轴。高表达HKII的细胞系比低表达HKII的细胞对3BP更敏感。3BP通过凋亡和坏死机制诱导Akt在苏氨酸-308位点快速磷酸化并导致细胞死亡。在较低葡萄糖浓度下培养的细胞对3BP表现出更大的抗性。HKII基因敲低的细胞对3BP的敏感性没有变化，这表明3BP的作用与HKII表达无关。这些结果强调了在考虑涉及代谢调节的治疗方法时，肿瘤微环境和葡萄糖可利用性的重要性。
