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主要研究内容及目标 

 

内容:主要从事真菌次级代谢产物抑制肿瘤发生的机理研究。研究该类代谢产物对肿瘤细胞自噬、凋亡、程序性坏死的影响以及引起上述细胞死亡间的关系。


目标:探求新的治疗肿瘤的靶点,从次级代谢产物中筛选出能够用于临床肿瘤治疗的药物。

 


主要研究成果简介

 

    通过研究发现,真菌来源的多硫二酮哌嗪类化合物11'-deoxyverticillin A(C42)能引起的细胞自噬和凋亡,而其引起的自噬早于凋亡发生。C42增加自噬受受体相互作用蛋白1(receptor-interacting protein 1,RIP1) 和聚(ADP-核糖)聚合酶 (poly ADP-ribose polymerase, PARP) 的调节。 另一研究发现,核因子kappa B (nuclear factor kappa B,NFkB) 调节C42引起的细胞凋亡和自噬。

代表性图片

Electron microscopy was performed on vehicle- (Ctrl) and C42-treated (0.25 μM, 6 h) HCT116 cells to detect the autophagosome formation. White arrow heads: the condensation and margination of the chromatin on nuclear membrane; left of low panel: swollen and degenerating mitochondria (white arrows), a vacuole with mitochondria inside (black arrow), a segment of double-membrane structure between a vacuole and mitochondrion (black arrow head); right of low panel: high-contrast image of the cell region indicated by white rectangle.

HCT116 cells were transfected with a plasmid expressing GFP-LC3. After 24 h, the cells were incubated for 6 h at 37°C in DMEM medium with DMSO (Ctrl) or C42 (0.25 μM). Following fixation, cells were stained with DAPI and visualized by confocal microscopy. In contrast to the C42-exposed cells, which showed increased punctate staining of GFP-LC3, GFP-LC3 staining remained diffuse in the control cells.

Immune electron microscopy was performed A431 cells (A) or isolated mitochondria of A431 cells (B) to detect the mitochondrial localized EGFR. Colloidal gold particles, which represent the EGFR, were clearly located within the mitochondria, while there is no staining in control cell. N-Ctrl: negative control. (C) GFP-EGFR expressing PAE were permeabilized and immunostained with anti-MtHsp70-Cy3, followed with Cy3-labeled secondary antibodies for imaging. The yellow color representes the overlay between red and green fluorescence.
(D) Fractionation of homogenized A431 cells with or without EGF (100 ng/ml, 1 h) and the resulting fractions were immunoblotted with the antibodies indicated. TH, total homogenate; Cyto/S, cytosol/S100; V-pellet, vesicular pellet; Hmmbp, heavy membrane pellet; P-mito: purified mitochondria.