Epidermal growth factor receptor mediated proliferation depends on increased lipid droplet density regulated via a negative regulatory loop with FOXO3/Sirtuin6.
Epidermal growth factor receptor mediated proliferation depends on increased lipid droplet density regulated via a negative regulatory loop with FOXO3/Sirtuin6.
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DOI：
10.1016/j.bbrc.2015.11.119
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发表时间：
2016-01-15
影响因子：
3.1
通讯作者：
Savkovic SD
中科院分区：
文献类型：
--
作者：
Penrose H;Heller S;Cable C;Makboul R;Chadalawada G;Chen Y;Crawford SE;Savkovic SD
结肠癌细胞的增殖部分由表皮生长因子受体（EGFR）信号传导介导，并且需要持续水平的细胞能量来满足其高代谢需求。细胞内脂滴（LD）是用于各种细胞功能的能量来源，并且它们在人类癌症中密度升高，但它们的调节和功能尚不清楚。在这里，在人类结肠癌细胞中，EGF刺激LD密度增加，这取决于EGFR表达和激活以及个体细胞的脂质合成能力。LD的增加通过抑制PI 3 K/mTOR和PGE 2合成而被阻断，支持其对选择的上游途径的依赖性。在结肠癌细胞中，FOXO 3转录因子的沉默导致SIRT 6（脂质合成的负调节因子）的下调，以及随后LD外壳蛋白PLIN 2的增加，这表明LD的增加取决于FOXO 3/SIRT 6的丢失。此外，EGF刺激FOXO 3/SIRT 6的损失，这是通过抑制上游途径以及脂质合成来阻断的，揭示了LD和FOXO 3/SIRT 6之间存在负调控环。升高的LD被EGF处理利用，并且通过抑制脂质合成或PLIN 2沉默来消耗它们显著减弱增殖。这种导致结肠癌细胞中LD密度升高的增殖性EGFR信号传导的新机制可能潜在地被治疗靶向用于治疗肿瘤进展。
The proliferation of colon cancer cells is mediated in part by epidermal growth factor receptor (EGFR) signaling and requires sustained levels of cellular energy to meet its high metabolic needs. Intracellular lipid droplets (LDs) are a source of energy used for various cellular functions and they are elevated in density in human cancer, yet their regulation and function are not well understood. Here, in human colon cancer cells, EGF stimulates increases in LD density, which depends on EGFR expression and activation as well as the individual cellular capacity for lipid synthesis. Increases in LDs are blockaded by inhibition of PI3K/mTOR and PGE2 synthesis, supporting their dependency on select upstream pathways. In colon cancer cells, silencing of the FOXO3 transcription factor leads to down regulation of SIRT6, a negative regulator of lipid synthesis, and consequent increases in the LD coat protein PLIN2, revealing that increases in LDs depend on loss of FOXO3/SIRT6. Moreover, EGF stimulates loss of FOXO3/SIRT6, which is blockaded by the inhibition of upstream pathways as well as lipid synthesis, revealing existence of a negative regulatory loop between LDs and FOXO3/SIRT6. Elevated LDs are utilized by EGF treatment and their depletion through the inhibition of lipid synthesis or silencing of PLIN2 significantly attenuates proliferation. This novel mechanism of proliferative EGFR signaling leading to elevated LD density in colon cancer cells could potentially be therapeutically targeted for the treatment of tumor progression.
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影响因子：
11.2
作者：
Wee, Susan;Jagani, Zainab;Stegmeier, Frank
通讯作者：
Stegmeier, Frank
DOI：
10.1016/j.bjoms.2012.11.009
发表时间：
2013-09-01
影响因子：
1.8
作者：
Breuel, Wiebke;Krause, Micaela;Harzer, Winfried
通讯作者：
Harzer, Winfried
影响因子：
5.5
作者：
McIntosh, Avery L.;Senthivinayagam, Subramanian;Atshaves, Barbara P.
通讯作者：
Atshaves, Barbara P.
影响因子：
9.2
作者：
Herms, Albert;Bosch, Marta;Ariotti, Nicholas;Reddy, Babu J. N.;Fajardo, Alba;Fernandez-Vidal, Andrea;Alvarez-Guaita, Anna;Fernandez-Rojo, Manuel Alejandro;Rentero, Carles;Tebar, Francesc;Enrich, Carlos;Geli, Maria-Isabel;Parton, Robert G.;Gross, Steven P.;Pol, Albert
通讯作者：
Pol, Albert
影响因子：
64.8
作者：
BURGERING, BMT;COFFER, PJ
通讯作者：
COFFER, PJ