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A naturally derived small molecule compound suppresses tumor growth and metastasis in mice by relieving p53-dependent repression of CDK2/Rb signaling and the Snail-driven EMT

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Chinese Journal of Natural Medicines 2024年第2期22卷 112-126页

作者： REN Boxue LI Yang DI Lei CHENG Ranran LIU Lijuan LI Hongmei LI Yi TANG Zhangrui YAN Yongming LU Tao FU Rong CHENG Yongxian WU Zhaoqiu State Key Laboratory of Natural Medicines Department of PharmacologySchool of PharmacyChina Pharmaceutical UniversityNanjing 211198China Institute for Inheritance-Based Innovation of Chinese Medicine School of Pharmaceutical SciencesShenzhen University Health Science CenterShenzhen 518060China

The tumor suppressor protein p53 is central to cancer biology,with its pathway reactivation emerging as a promising therapeutic strategy in *** study introduced LZ22,a novel compound that selectively inhibits the growth,migration,and metastasis of tumor cells expressing wild-type p53,demonstrating ineffectiveness in cells devoid of p53 or those expressing mutant ***22’s mechanism of action involves a high-affinity interaction with the histidine-96 pocket of the MDM2 *** interaction disrupted the MDM2-p53 binding,consequently stabilizing p53 by shielding it from proteasomal ***22 impeded cell cycle progression and diminished cell proliferation by reinstating the p53-dependent suppression of the CDK2/Rb signaling ***,LZ22 alleviated the p53-dependent repression of Snail transcription factor expression and its consequent EMT,effectively reducing tumor cell migration and distal ***,LZ22 administration in tumor-bearing mice did not manifest notable side *** findings position LZ22 as a structurally unique reactivator of p53,offering therapeutic promise for the management of human cancers with wild-type TP53.

关键词： LZ22 Wild-type p53 p53 Reactivator Snail-driven EMT tumor growth and metastasis

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Circadian Clock Gene NPAS2 promotes reprogramming of glucose metabolism in Hepatocellular Carcinoma cells

Circadian Clock Gene NPAS2 promotes reprogramming of glucose...

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2018年中国肿瘤标志物学术大会暨第十二届肿瘤标志物青...

作者： Jibin Li Peng Yuan Jiansheng Zhang Jing Zhao Tao Yang Xiaoyu Long Yiran Hou Feng Zhou Hongxin Zhang Jinliang Xing State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic Medicine the Fourth Military Medical University Department of Pain Treatment Tangdu Hospital the Fourth Military Medical University

Emerging evidences show that dysregulation of circadian genes is closely associated with tumor development by participating in the cancer hallmarks of proliferative signaling maintenance, cell death resistance, replicative immortality and metastasis activation. However, whether circadian genes regulates the metabolism reprogramming required for tumor cell proliferation and invasion is ***, we show that NPAS2, one of the core circadian molecules, significantly contributed to the reprogramming of glucose metabolism mainly by two mechanisms. On one hand, NPAS2 upregulated the expression of glycolytic genes HK2, PKM2 and Glut1, which directly activated the aerobic glycolysis. On the other hand, NPAS2 downregulated peroxisome proliferator-activated receptor gamma coactivator 1 alpha（PGC-1α）, a crucial regulator of mitochondrial biogenesis, which in turn directly repressed mitochondrial respiration. Mechanistically, HIF-1 a was found to be a direct transcriptional target of NPAS2, which mediated both the upregulation of glycolytic genes of HK2,PKM2 and Glut1, and downregulation of mitochondrial regulator PGC-1α in HCC cells. Moreover, in vitro and in vivo assays indicated that the NPAS2-mediated reprogramming of glucose metabolism reprogramming played a critical role in tumor growth and metastasis of ***: Our findings demonstrate that NPAS2 plays a critical role in the regulation of tumor cell glucose metabolism reprogramming, which indicates that NPAS2 may serve as an important therapeutic target to normalize glucose metabolic aberrations responsible for HCC progression.

关键词： neuronal PAS domain protein 2 circadian rhythm Glycolysis Mitochondrial respiration Hepatocellular carcinoma tumor growth and metastasis

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Circadian Clock Gene NPAS2 promotes reprogramming of glucose metabolism in Hepatocellular Carcinoma cells

Circadian Clock Gene NPAS2 promotes reprogramming of glucose...

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2017年中国肿瘤标志物学术大会暨第十一届肿瘤标志物青...

作者： Jibin Li Peng Yuan Hongxin Zhang Jinliang Xing State Key Laboratory of Cancer Biology and Experimental Teaching Center of Basic Medicine the Fourth Military Medical University Department of Pain Treatment Tangdu Hospitalthe Fourth Military Medical University

Aims: Emerging evidences show that dysregulation of circadian genes is closely associated with tumor development by participating in the cancer hallmarks of proliferative signaling maintenance, cell death resistance, replicative immortality and metastasis activation. However, whether circadian genes regulates the metabolism reprogramming required for tumor cell proliferation and invasion is unknown. Methods: In the present study, we systematically investigated the role of NPAS2 in the reprogramming of glucose metabolism, as well as its role in the growth and metastasis of HCC cells both in vitro and in vivo. Moreover, the molecular meachnisms governing NPAS2-mediated glucose metabolismreprogramming were further explored. Results: Our results showed that NPAS2, one of the core circadian molecules, significantly contributed to the reprogramming of glucose metabolism through a Hif-1 a-dependent way in HCC cells mainly by two mechanisms. On one hand, NPAS2 upregulated the expression of glycolytic genes HK2, PKM2 and Glut1 by activating transcription of Hif-1 a, which in turn directly activated the aerobic glycolysis. On the other hand, NPAS2 downregulated Peroxisome proliferator-activated receptor gamma coactivator 1 alpha（PGC-1α） by activating transcription of Hif-1 a, which in turn directly repressed mitochondrial biogenesis and respiration. Moreover, in vitro and in vivo assays indicated that the NPAS2-mediated reprogramming of glucose metabolism reprogramming played a critical role in tumor growth and metastasis of HCC. Conclusion: Our findings demonstrate that NPAS2 plays a critical role in tumor cell metabolism reprogramming regulation, which indicates that NPAS2 may serve as an important therapeutic target to normalize metabolic aberrations responsible for HCC progression.

关键词： neuronal PAS domain protein 2 circadian rhythm Glycolysis Mitochondrial respiration Hepatocellular carcinoma tumor growth and metastasis

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