美國(guó)猶他大學(xué)（the University of Utah）Huntsman癌癥研究所的研究人員,，提出了一個(gè)新的想法,，他們認(rèn)為腫瘤細(xì)胞的能量來源就是糖,，這項(xiàng)研究或許也對(duì)其他疾病,，例如：糖尿病,，也會(huì)有更多的了解,，此研究表于近期的Proceedings of the National Academy of Sciences期刊,。
Ayer表示：自1923年,，研究人員就已經(jīng)知道腫瘤細(xì)胞會(huì)比正常細(xì)胞使用更多的葡萄糖（glucose）,，而這份研究則協(xié)助我們了解這個(gè)過程是如何發(fā)生的，以及如何利用糖類來達(dá)到控制腫瘤生長(zhǎng)的目的,。研究人員表示：在腫瘤細(xì)胞或正常細(xì)胞生長(zhǎng)的過程中,，都需要利用到葡萄糖及谷胺酰胺（glutamine），長(zhǎng)久以來,，大家都認(rèn)為這兩種細(xì)胞生長(zhǎng)的必要成份毫不相關(guān),，但是，Ayer研究團(tuán)隊(duì)卻發(fā)現(xiàn)它們是相互依賴的,，研究中發(fā)現(xiàn)當(dāng)限制了glutamine的可利用性時(shí),，glucose也被停止使用，從實(shí)質(zhì)上來講,，細(xì)胞沒有了glutamine,，也就喪失了glucose，于是腫瘤細(xì)胞的生長(zhǎng)也就停止了,。
研究人員將目標(biāo)集中在MondoA蛋白上,，這個(gè)蛋白能調(diào)控基因的表現(xiàn)與否，當(dāng)glutamine存在,，MondoA就會(huì)阻止TXNIP基因（注：TXNIP基因?yàn)橐粋€(gè)抑癌基因，suppressor）的表現(xiàn),，此時(shí)細(xì)胞就會(huì)被允許利用glucose,，以驅(qū)動(dòng)腫瘤的生長(zhǎng)。目前,，研究團(tuán)隊(duì)正以MondoA,、TXNIP或是glutamine的利用性作為標(biāo)靶，找尋具潛力治療癌癥的新藥,，下一步將進(jìn)行動(dòng)物試驗(yàn),，以確認(rèn)這個(gè)概念的真實(shí)性與應(yīng)用性。(生物谷www.bioon.com)
Bioon推薦原始出處：
PNAS September 1, 2009 vol. 106 no. 35 14878-14883
Glutamine-dependent anapleurosis dictates glucose uptake and cell growth by regulating MondoA transcriptional activity
Mohan R. Kaadigea, Ryan E. Looperb, Sadhaasivam Kamalanaadhana and Donald E. Ayera,1
aHuntsman Cancer Institute, Department of Oncological Sciences and
bDepartment of Chemistry, University of Utah, 2000 Circle of Hope, Room 4365, Salt Lake City, UT 84112-5550
Glucose and glutamine are abundant nutrients required for cell growth, yet how cells sense and adapt to changes in their levels is not well understood. The MondoA transcription factor forms a heterocomplex with its obligate partner Mlx to regulate ≈75% of glucose-dependent transcription. By mediating glucose-induced activation of thioredoxin-interacting protein (TXNIP), MondoA:Mlx complexes directly repress glucose uptake. We show here that glutamine inhibits transcriptional activation of TXNIP by triggering the recruitment of a histone deacetylase-dependent corepressor to the amino terminus of MondoA. Therefore, in the presence of both glucose and glutamine, TXNIP expression is low, which favors glucose uptake and aerobic glycolysis; the Warburg effect. Consistent with MondoA functioning upstream of TXNIP, MondoA knockdown reduces TXNIP expression, elevates glucose uptake and stimulates cell proliferation. Although glutamine has many intracellular fates, a cell permeable analog of a tricarboxylic acid cycle (TCA) intermediate, α-ketoglutarate, also blocks the transcriptional activity of MondoA at the TXNIP promoter and stimulates glucose uptake. Together our data suggest that glutamine-dependent mitochondrial anapleurosis dictates glucose uptake and aerobic glycolysis by blocking MondoA:Mlx-dependent transcriptional activation of TXNIP. We propose that this previously unappreciated coordination between glutamine and glucose utilization defines a metabolic checkpoint that restricts cell growth when subthreshold levels of these essential nutrients are available.
