6月15日，Cancer Research雜志在線報(bào)道了在大腸癌中,，陷窩蛋白-1通過(guò)刺激HMGA1介導(dǎo)的GLUT3轉(zhuǎn)錄，增加有氧糖酵解。
陷窩蛋白-1（CAV1）在多種人類惡性腫瘤中作為生長(zhǎng)抑制因子,，但在許多晚期癌癥中其表達(dá)升高，提示其在腫瘤進(jìn)展中的致癌開(kāi)關(guān)作用,。為理解CAV1增長(zhǎng)促進(jìn)作用的分子基礎(chǔ),，研究者分析了其在腫瘤生長(zhǎng)中的表達(dá)狀態(tài)和在分化中的作用，以及它對(duì)大腸癌腫瘤的生長(zhǎng)和糖代謝的影響,。在很大一部分原發(fā)腫瘤和細(xì)胞系中,，可檢測(cè)到CAV1的異常升高。這與啟動(dòng)子CpG位點(diǎn)的低甲基化緊密相關(guān),。
升高CAV1的消耗,，導(dǎo)致AMPK活化和隨后的p53依賴的G1細(xì)胞周期阻滯和細(xì)胞自噬,。這表明升高CAV1可能促進(jìn)ATP生成。此外,，CAV1的消耗可下調(diào)葡萄糖的攝取,，乳酸堆積和細(xì)胞內(nèi)ATP水平。這提示,，CAV1增強(qiáng)有氧糖酵解,。相應(yīng)的，研究結(jié)果表明CAV1通過(guò)一個(gè)GLUT3啟動(dòng)子內(nèi)的HMGA1結(jié)合位點(diǎn),，刺激GLUT3的轉(zhuǎn)錄,。
研究還發(fā)現(xiàn)，HMGA1與GLUT3啟動(dòng)子相互作用并活化它,，而CAV1通過(guò)加強(qiáng)HMGA1的核定位來(lái)增加其活力,。 HMGA1的異位表達(dá)增加葡萄糖的攝取，而其表達(dá)下調(diào)導(dǎo)致AMPK激活,。此外,，共轉(zhuǎn)染CAV1和HMGA1可誘導(dǎo)GLUT3強(qiáng)烈表達(dá)。GLUT3過(guò)度表達(dá)主要表現(xiàn)在高水平表達(dá)CAV1和HMGA1的腫瘤中,?？傊@些數(shù)據(jù)顯示,，升高的CAV1通過(guò)HMGA1介導(dǎo)的GLUT3轉(zhuǎn)錄上調(diào)葡萄糖的攝取和ATP的生產(chǎn),。這表明，CAV1提高有氧糖酵解可能導(dǎo)致腫瘤細(xì)胞的生長(zhǎng)優(yōu)勢(shì),。（生物谷bioon.com）
doi:10.1016/j.cell.2011.10.017
PMC:
PMID:
Caveolin-1 Increases Aerobic Glycolysis in Colorectal Cancers by Stimulating HMGA1-Mediated GLUT3 Transcription
Sung-Gil Chi1,*, Tae-Kyu Ha1, Nam-Gu Her1, Min-Goo Lee1, Byung-Kyu Ryu1, Jin-Hee Lee1, Jikhyon Han1, Seong-In Jeong1, Min-Ju Kang1, Nam-Hoon Kim2, and Hyo-Jong Kim3
Caveolin-1 (CAV1) acts as a growth suppressor in various human malignancies but its expression is elevated in many advanced cancers, suggesting the oncogenic switch of its role during tumor progression. To understand the molecular basis for the growth-promoting function of CAV1, we characterized its expression status, differential roles for tumor growth and effect on glucose metabolism in colorectal cancers. Abnormal elevation of CAV1 was detected in a substantial fraction of primary tumors and cell lines and tightly correlated with promoter CpG sites hypomethylation. Depletion of elevated CAV1 led to AMPK activation followed by a p53-dependent G1 cell cycle arrest and autophagy, suggesting that elevated CAV1 may contribute to ATP generation. Furthermore, CAV1 depletion down-regulated glucose uptake, lactate accumulation and intracellular ATP level, supporting that aerobic glycolysis is enhanced by CAV1. Consistently, CAV1 was shown to stimulate GLUT3 transcription via a HMGA1-binding site within the GLUT3 promoter. HMGA1 was found to interact with and activate the GLUT3 promoter and CAV1 increased the HMGA1 activity by enhancing its nuclear localization. Ectopic expression of HMGA1 increased glucose uptake while its knockdown caused AMPK activation. In addition, GLUT3 expression was strongly induced by co-transfection of CAV1 and HMGA1 and its overexpression was observed predominantly in tumors harboring high levels of CAV1 and HMGA1. Together, these data show that elevated CAV1 up-regulates glucose uptake and ATP production through HMGA1-mediated GLUT3 transcription, suggesting that CAV1 may render tumor cells growth advantages by enhancing aerobic glycolysis.
