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JCI:研究证实有氧糖酵解并非癌变结果

来源:生物谷 2013-12-22 21:29

2013年12月22日讯 /生物谷BIOON/--近日,伯克利实验室生命科学部杰出科学家Mina Bissell等人证实:有氧糖酵解不是恶性细胞癌变的结果,其本身就是一个癌性事件。糖摄取的急剧增加可能是肿瘤发生的一个原因,Bissell说。此外,通过一系列细致的分析,科学家们已经发现了增加葡萄糖摄取的两个新的途径,本身也可能激活其他致癌途径。

这一发现揭示了癌症诊断和治疗可能的新靶标。与Bissell一起,日本博士后研究员Yasuhito Onodera检查人乳腺癌细胞的葡萄糖转运蛋白的表达。他关注的重点是葡萄糖转运蛋白GLUT3,恶性肿瘤细胞GLUT3的表达量是在非恶性乳腺细胞的400倍以上。

这项研究使用三维培养法,使乳腺细胞形成结构单元,使得恶性细胞能繁殖形成瘤状群落。Bissell说:我们发现,GLUT3在非恶性乳腺癌细胞中的过表达激活已知的致癌信号传导途径,并导致组织极性的丧失和癌细胞生长的开始。相反,GLUT3在恶性细胞的减少导致表型逆转,致癌基因信号传导途径被抑制,并且细胞表现为非恶性状态,即使它们仍然含有恶性基因组。

40多年前,Bissell开始探索有氧糖酵解和恶性细胞的关系。她好奇于Warburg效应,Warburg效应理论认为有氧糖酵解增加是致癌原因,而不是癌症的症状。但这个假设存在争议,因为许多研究人员发现在正常细胞中也存在有氧糖酵解。即使是现在,大多数人都认为,细胞糖摄取的增加是肿瘤细胞代谢的强烈需求,而不是恶变的原因。

Bissell认为:证实葡萄糖摄取在乳腺癌发展中的积极作用,只可能通过三维培养分析来揭示。Bissell说:在我们的三维培养测定中,葡萄糖摄取和代谢决定致癌信号的活性以及恶性、非恶性乳腺上皮细胞的形态。

Bissell认为他们的发现有助于解释为什么高血糖疾病如肥胖和糖尿病可提高乳腺癌和其他癌症的风险。此外,这些结果也可能有助于解释为什么抗糖尿病药,如二甲双胍能降低癌症风险和死亡率。

这项研究结果已经发表在Journal of Clinical Investigation杂志上。(生物谷Bioon.com)

 

Increased sugar uptake promotes oncogenesis via EPAC/RAP1 and O-GlcNAc pathways.

Onodera Y, Nam JM, Bissell MJ.

There is a considerable resurgence of interest in the role of aerobic glycolysis in cancer; however, increased glycolysis is frequently viewed as a consequence of oncogenic events that drive malignant cell growth and survival. Here we provide evidence that increased glycolytic activation itself can be an oncogenic event in a physiologically relevant 3D culture model. Overexpression of glucose transporter type 3 (GLUT3) in nonmalignant human breast cells activated known oncogenic signaling pathways, including EGFR, β1 integrin, MEK, and AKT, leading to loss of tissue polarity and increased growth. Conversely, reduction of glucose uptake in malignant cells promoted the formation of organized and growth-arrested structures with basal polarity, and suppressed oncogenic pathways. Unexpectedly and importantly, we found that unlike reported literature, in 3D the differences between "normal" and malignant phenotypes could not be explained by HIF-1α/2α, AMPK, or mTOR pathways. Loss of epithelial integrity involved activation of RAP1 via exchange protein directly activated by cAMP (EPAC), involving also O-linked N-acetylglucosamine modification downstream of the hexosamine biosynthetic pathway. The former, in turn, was mediated by pyruvate kinase M2 (PKM2) interaction with soluble adenylyl cyclase. Our findings show that increased glucose uptake activates known oncogenic pathways to induce malignant phenotype, and provide possible targets for diagnosis and therapeutics.

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