Zhongguang Luo

Fudan University, Shanghai, Shanghai Shi, China

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Publications (6)33.58 Total impact

  • Source
    Yanchun Wang · Zhongguang Luo · Yongfu Pan · Weige Wang · Xiaoyan Zhou · Lak Shin Jeong · Yiwei Chu · Jie Liu · Lijun Jia ·
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    ABSTRACT: Recent studies indicate that post-translational protein neddylation is required for the maintenance of cell viability in several lymphoma cell lines, while inhibition of the neddylation pathway with an NEDD8-activating enzyme (NAE) inhibitor MLN4924 induces apoptosis in lymphoma cells. However, the mechanism by which neddylation inhibition induces apoptosis in lymphoma cells has not been fully elucidated. Moreover, it is unknown whether neddylation inhibition triggers non-apoptotic cell-killing responses, such as cell senescence, in lymphoma cells. Here, we report that MLN4924 specifically inhibited protein neddylation, inactivated cullin-RING E3 ligase (CRL), the best-known neddylation substrate, and induced the accumulation of tumor-suppressive CRL substrates in lymphoma cells. Moreover, MLN4924 potently suppressed the growth of lymphoma cells by inducing G2 cell-cycle arrest, followed by apoptosis or senescence in a cell-line dependent manner. MLN4924-induced apoptosis was mediated by intrinsic apoptotic signaling with substantial up-regulation of pro-apoptotic Bik and Noxa as well as down-regulation of anti-apoptotic XIAP, c-IAP1 and c-IAP2, while senescence induction upon neddylation inhibition seemed dependent on the expression of tumor suppressor p21/p27. Together, these findings expand our understanding on how lymphoma cells respond to neddylation inhibition and support the development of neddylation inhibitors (e.g. MLN4924) for the treatment of lymphoma.
    Cancer biology & therapy 03/2015; 16(3). DOI:10.1080/15384047.2014.1003003 · 3.07 Impact Factor
  • Jun Zhang · Miao Wang · Zuowei Zhang · Zhongguang Luo · Fei Liu · Jie Liu ·
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    ABSTRACT: Liver fibrosis may lead to portal hypertension, liver failure or hepatocellular carcinoma, and predominantly results from the proliferation and activation of hepatic stellate cells. OSU‑03012, a non‑cyclooxygenase‑inhibiting celecoxib derivative, has been previously demonstrated to promote apoptosis in certain cell types, however, its function in hepatic fibrosis remains unclear. In the current study, the inhibitory effect of OSU‑03012 on the proliferation of the LX2 human hepatic stellate cell line was evaluated by cell counting kit‑8 assay. Reverse transcription‑quantitative polymerase chain reaction was performed in order to examine the expression of α‑smooth muscle actin and type I collagen, which are representative of LX2 cell activation. The senescence of LX2 cells was measured by senescence‑associated β‑galactosidase staining, and the cell cycle and apoptosis levels were assessed by flow cytometry. The impact of senescence‑associated signaling on protein expression was assessed by western blot analysis. OSU‑03012 was observed to inhibit cell proliferation and prevent the secretion of profibrotic factors in LX2 cells in a dose‑dependent manner. Furthermore, the results demonstrated that OSU‑03012 inhibited the proliferation and activation of LX2 via the induction of cell senescence at the G1 phase, rather than via cell apoptosis. The induction of senescence may be via the upregulation of p16, p21 and p27. In conclusion, the current study provided insight into the pharmacological mechanisms of OSU‑03012 in preventing the proliferation and activation of hepatic stellate cells through cell senescence. The current study supports the theory that OSU‑03012 is a novel agent for potential use against liver fibrosis.
    Molecular Medicine Reports 12/2014; 11(4). DOI:10.3892/mmr.2014.3048 · 1.55 Impact Factor
  • Bin Lu · Jiucun Wang · Jun Zhang · Xiaojiao Zhang · Dongqin Yang · Lijun Wu · Zhongguang Luo · Yanyun Ma · Qi Zhang · Yunfang Ma · Xiaoyu Pei · Hua Yu · Jie Liu ·
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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; 46(2). DOI:10.1093/abbs/gmt130 · 2.19 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; 12(10). DOI:10.1158/1535-7163.MCT-12-1245 · 5.68 Impact Factor
  • Source
    Zhongguang Luo · Yongfu Pan · Lak Shin Jeong · Jie Liu · Lijun Jia ·
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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). DOI:10.4161/auto.21484 · 11.75 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. DOI:10.1158/0008-5472.CAN-12-0388 · 9.33 Impact Factor

Publication Stats

68 Citations
33.58 Total Impact Points


  • 2012-2015
    • Fudan University
      • • Department of Immunology
      • • School of Life Sciences
      Shanghai, Shanghai Shi, China
  • 2013
    • University of Texas MD Anderson Cancer Center
      • Department of Experimental Therapeutics
      Houston, Texas, United States