Zhongguang Luo

Fudan University, Shanghai, Shanghai Shi, China

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Publications (4)28.73 Total impact

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    ABSTRACT: Hepatocellular carcinoma (HCC) is one of the most malignant cancers in the world. Molecular probes that can recognize biomarkers specific for HCC are urgently needed to improve the sensitivity and specificity of early diagnosis. A recent study has applied the method of systematic evolution of ligands by exponential enrichment and produced several aptamers that can bind specifically to mouse liver cancer cells and tissues. However, the binding affinity to human liver cancer has not been fully identified. Using human-derived hepatoma cell line HepG2 as positive target cell line and normal hepatocyte cell line HL-7702 as negative one, we obtained an aptamer HA09 that could specifically bind to human liver cancer cells with Kd in the nanomolar range and recognize paraffin-embedded human HCC tissues. This aptamer may facilitate the discovery of novel biomarkers and serve as an ideal molecular probe for intracellular delivery with both diagnostic and therapeutic implications.
    Acta Biochimica et Biophysica Sinica 12/2013; · 1.81 Impact Factor
  • Haiquan Lu, Xinqun Li, Zhongguang Luo, Jie Liu, Zhen Fan
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    ABSTRACT: Hypoxia-inducible factor-1 (HIF-1) plays a critical role in reprogramming cancer metabolism towards aerobic glycolysis (i.e., the Warburg effect), which is critical to supplying cancer cells with the biomass needed for proliferation. Previous studies have shown that cetuximab, an epidermal growth factor receptor-blocking monoclonal antibody, downregulates the alpha subunit of HIF-1 (HIF-1α) through the inhibition of epidermal growth factor receptor downstream cell signaling and that downregulation of HIF-1α is required for cetuximab-induced antiproliferative effects. However, the mechanism underlying these actions has yet to be identified. In this study, we used the Seahorse XF96 extracellular flux analyzer to assess the effect of cetuximab treatment on changes in glycolysis and mitochondrial respiration, the two major energy-producing pathways, in live cells. We found that cetuximab downregulated lactate dehydrogenase A (LDH-A) and inhibited glycolysis in cetuximab-sensitive head and neck squamous cell carcinoma (HNSCC) cells in a HIF-1α downregulation-dependent manner. HNSCC cells with acquired cetuximab resistance expressed a high level of HIF-1α and were highly glycolytic. Overexpression of a HIF-1α mutant (HIF-1α/ΔODD) conferred resistance to cetuximab-induced G1-phase cell cycle arrest, which could be overcome by knockdown of LDH-A expression. Inhibition of LDH-A activity with oxamate enhanced the response of cetuximab-resistant cells to cetuximab. Cetuximab had no noticeable inhibitory effect on glycolysis in nontransformed cells. These findings provide novel mechanistic insights into cetuximab-induced cell cycle arrest from the perspective of cancer metabolism and suggest novel strategies for enhancing cetuximab response.
    Molecular Cancer Therapeutics 08/2013; · 5.60 Impact Factor
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    ABSTRACT: The multiunit Cullin (CUL)-RING E3 ligase (CRL) controls diverse biological processes by targeting a mass of substrates for ubiquitination and degradation, whereas its dysfunction causes carcinogenesis. Post-translational neddylation of CUL, a process triggered by the NEDD8-activating enzyme E1 subunit 1 (NAE1), is required for CRL activation. Recently, MLN4924 was discovered via a high-throughput screen as a specific NAE1 inhibitor and first-in-class anticancer drug. By blocking CUL neddylation, MLN4924 inactivates CRL and causes the accumulation of CRL substrates that trigger cell cycle arrest, senescence and/or apoptosis to suppress the growth of cancer cells in vitro and in vivo. Recently, we found that MLN4924 also triggers protective autophagy in response to CRL inactivation. MLN4924-induced autophagy is attributed partially to the inhibition of mechanistic target of rapamycin (also known as mammalian target of rapamycin, MTOR) activity by the accumulation of the MTOR inhibitory protein DEPTOR, as well as reactive oxygen species (ROS)-induced stress. Moreover, the blockage of autophagy response enhances apoptosis in MLN4924-treated cells. Together, our findings not only reveal autophagy as a novel cellular response to CRL inactivation by MLN4924, but also provide a piece of proof-of-concept evidence for combination therapy with MLN4924 and autophagy inhibitors to enhance therapeutic efficacy.
    Autophagy 11/2012; 8(11). · 12.04 Impact Factor
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    ABSTRACT: Posttranslational neddylation of cullins in the Cullin-Ring E3 ligase (CRL) complexes is needed for proteolytic degradation of CRL substrates, whose accumulation induces cell-cycle arrest, apoptosis, and senescence. The Nedd8-activating enzyme (NAE) is critical for neddylation of CRL complexes and their growth-promoting function. Recently, the anticancer small molecule MLN4924 currently in phase I trials was determined to be an inhibitor of NAE that blocks cullin neddylation and inactivates CRL, triggering an accumulation of CRL substrates that trigger cell-cycle arrest, apoptosis, and senescence in cancer cells. Here, we report that MLN4924 also triggers autophagy in response to CRL inactivation and that this effect is important for the ability of MLN4924 to suppress the outgrowth of liver cancer cells in vitro and in vivo. MLN4924-induced autophagy was attributed partially to inhibition of mTOR activity, due to accumulation of the mTOR inhibitory protein Deptor, as well as to induction of reactive oxygen species stress. Inhibiting autophagy enhanced MLN4924-induced apoptosis, suggesting that autophagy is a survival signal triggered in response to CRL inactivation. In a xenograft model of human liver cancer, MLN4924 was well-tolerated and displayed a significant antitumor effect characterized by CRL inactivation and induction of autophagy and apoptosis in liver cancer cells. Together, our findings support the clinical investigation of MLN4924 for liver cancer treatment and provide a preclinical proof-of-concept for combination therapy with an autophagy inhibitor to enhance therapeutic efficacy.
    Cancer Research 05/2012; 72(13):3360-71. · 9.28 Impact Factor