Ke Tang

Huazhong University of Science and Technology

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Jingwei Ma

Huazhong University of Science and Technology

Bo Huang

Hunan University of Traditional Chinese Medicine

Jiadi Lv

Chinese Academy of Medical Sciences & Peking Union Medical College

Yuying Liu

Xuzhou Medical College

Pingwei Xu

Wenzhou Medical University

Xiaoyu Liang

Chinese Academy of Medical Sciences & Peking Union Medical College

Huafeng Zhang

Huazhong University of Science and Technology

Yabo Zhou

Chinese Academy of Medical Sciences & Peking Union Medical College

Bo Huang

University of Electronic Science and Technology of China

Huafeng Zhang

Tianjin Medical University General Hospital

Cooperative Institutions

Huazhong University of Science and Technology

202

Chinese Academy of Medical Sciences & Peking Union Medical College

155

Central South University

114

Chinese Academy of Sciences

Shanghai Jiao Tong University

Sichuan University

Tongji Hospital

Sun Yat-sen University

Union Hospital

University of Chinese Academy of Sciences

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Hypoxia-reprogrammed tricarboxylic acid cycle promotes the growth of human breast tumorigenic cells

Oncogene (2019)

Ke Tang Yuandong Yu Liyan Zhu Pingwei Xu Jie Chen

Clinical applications of antiangiogenic agents profoundly affect tumor cell behaviors via the resultant hypoxia. To date, how the hypoxia regulates tumor cells remains unclear. Here, we show that hypoxia promotes the growth of human breast tumorigenic cells that repopulate tumors [tumor-repopulating cells (TRCs)] in vitro and in vivo. This stimulating effect is ascribed to hypoxia-induced reactive oxygen species (ROS) that activates Akt and NF-κB, dependent on the attenuated tricarboxylic acid (TCA) cycle. We find that fumarate is accumulated in the TCA cycle of hypoxic TRCs, leading to glutathione succination, NADPH/NADP+ decrease, and an increase in ROS levels. Mechanistically, hypoxia-increased HIF-1α transcriptionally downregulates the expression of mitochondrial phosphoenolpyruvate carboxykinase (PCK2), leading to TCA cycle attenuation and fumarate accumulation. These findings reveal that hypoxia-reprogrammed TCA cycle promotes human breast TRCs growth via a HIF-1α-downregulated PCK2 pathway, implying a need for a combination of an antiangiogenic therapy with an antioxidant modulator.

Hypoxia

Tumor Hypoxia

10.1038/s41388-019-0932-1

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Citations (54)

Gasdermin E–mediated target cell pyroptosis by CAR T cells triggers cytokine release syndrome

Science Immunology (2020)

Yuying Liu Yiliang Fang Xinfeng Chen Zhenfeng Wang Xiaoyu Liang

Cytokine release syndrome (CRS) counteracts the effectiveness of chimeric antigen receptor (CAR) T cell therapy in cancer patients, but the mechanism underlying CRS remains unclear. Here, we show that tumor cell pyroptosis triggers CRS during CAR T cell therapy. We find that CAR T cells rapidly activate caspase 3 in target cells through release of granzyme B. The latter cleaves gasdermin E (GSDME), a pore-forming protein highly expressed in B leukemic and other target cells, which results in extensive pyroptosis. Consequently, pyroptosis-released factors activate caspase 1 for GSDMD cleavage in macrophages, which results in the release of cytokines and subsequent CRS. Knocking out GSDME, depleting macrophages, or inhibiting caspase 1 eliminates CRS occurrence in mouse models. In patients, GSDME and lactate dehydrogenase levels are correlated with the severity of CRS. Notably, we find that the quantity of perforin/granzyme B used by CAR T cells rather than existing CD8+ T cells is critical for CAR T cells to induce target cell pyroptosis.

Pyroptosis

Granzyme

10.1126/sciimmunol.aax7969

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Citations (423)

Fra-1 is upregulated in gastric cancer tissues and affects the PI3K/Akt and p53 signaling pathway in gastric cancer

International Journal of Oncology (2015)

Junyu He Guangchao Zhu Lu Gao Pan Chen Yuehua Long

Gastric cancer is an aggressive disease that continues to have a daunting impact on global health. Fra-1 (FOSL1) plays important roles in oncogenesis in various malignancies. We investigated the expression of Fra-1 in gastric cancer (GC) tissues by qPCR, immunohistochemistry (IHC) and western blot technologies. The results showed that Fra-1 was overexpressed in gastric cancer tissues compared with the adjacent non‑cancerous tissues. To explore the possible mechanism of Fra-1 in GC, we elucidated the effect of Fra-1 in the apoptosis and cell cycle of gastric cancer cells, AGS, and found that a considerable decrease in apoptotic cells and increase of S phase rate were observed for AGS cells with Fra-1 overexpession. We identified and confirmed that Fra-1 affected the expression level of CTTN and EZR in vitro through LC-MS/MS analyses and western blot technology. Furthermore, we found that Fra-1 was correlated with dysregulation PI3K/Akt and p53 signaling pathway in gastric cancer tissues in vitro. Moreover, we found that Fra-1 overexpression affected the expression of PI3K, Akt, MDM2 and p53 in vivo. In summary, our results suggest that Fra-1 is upregulated in gastric cancer tissues and plays its function by affecting the PI3K/Akt and p53 signaling pathway in gastric cancer.

10.3892/ijo.2015.3146

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Citations (49)

LPLUNC1 suppresses IL-6-induced nasopharyngeal carcinoma cell proliferation via inhibiting the Stat3 activation

Oncogene (2013)

Qianjin Liao Zhaoyang Zeng Xiaokui Guo Xinyi Li Fengcai Wei

10.1038/onc.2013.161

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Citations (123)

Delivery of chemotherapeutic drugs in tumour cell-derived microparticles

Nature Communications (2012)

Ke Tang Yi Zhang Huafeng Zhang Pingwei Xu Jing Liu

Chemotherapeutic drugs

Efflux

10.1038/ncomms2282

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Citations (412)

Delivery of oncolytic adenovirus into the nucleus of tumorigenic cells by tumor microparticles for virotherapy

Biomaterials (2016)

Ran Li Tan Xiaohua Yanchun Li Huafeng Zhang Ruihua Ma

Virotherapy

Oncolytic adenovirus

10.1016/j.biomaterials.2016.02.025

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Citations (84)

[Expression and location of UBAP1 protein associated with nasopharyngeal carcinoma].

PubMed (2005)

Zhaoyang Zeng Jun Qian Wei Xiong Yanhong Zhou Wenling Zhang

To analyze the expression and location of coding protein of UBAP1 gene and to understand the relationship between the expression pattern of the protein and cell carcinogenesis.Bioinformatics was used to analyze the protein character to provide an available clue of subsequent research. The codon frame cDNA was amplified by PCR, and subcloned into enhance green fluorescence protein (EGFP) of pEGFP-C2. The recombinant plasmid was transfected into HNE1 cells. The expression of coding protein was observed by fluorescence microscopy.The expressed GFP-fusion protein generated striking green fluorescence in the cytoplasm in HNE1 cells. EGFP/UBAP1 was expressed and existed mainly in the nuclear, especially accumulated on the nuclear envelope.The expression difference in HNE1 might be related to the carcinogenesis of NPC.

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Cell softness renders cytotoxic T lymphocytes and T leukemic cells resistant to perforin-mediated killing

Nature Communications (2024)

Yabo Zhou Dianheng Wang Li Zhou Nannan Zhou Zhenfeng Wang

Abstract Mechanical force contributes to perforin pore formation at immune synapses, thus facilitating the cytotoxic T lymphocytes (CTL)-mediated killing of tumor cells in a unidirectional fashion. How such mechanical cues affect CTL evasion of perforin-mediated autolysis remains unclear. Here we show that activated CTLs use their softness to evade perforin-mediated autolysis, which, however, is shared by T leukemic cells to evade CTL killing. Downregulation of filamin A is identified to induce softness via ZAP70-mediated YAP Y357 phosphorylation and activation. Despite the requirements of YAP in both cell types for softness induction, CTLs are more resistant to YAP inhibitors than malignant T cells, potentially due to the higher expression of the drug-resistant transporter, MDR1, in CTLs. As a result, moderate inhibition of YAP stiffens malignant T cells but spares CTLs, thus allowing CTLs to cytolyze malignant cells without autolysis. Our findings thus hint a mechanical force-based immunotherapeutic strategy against T cell leukemia.

CTL*

10.1038/s41467-024-45750-w

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Citations (7)

Ammonia-induced lysosomal and mitochondrial damage causes cell death of effector CD8+ T cells

Nature Cell Biology (2024)

Huafeng Zhang Jincheng Liu Yuan Wu Qian Zhang Xiao Luo

10.1038/s41556-024-01503-x

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Citations (9)

Cell Softness Prevents Cytolytic T-cell Killing of Tumor-Repopulating Cells

Cancer Research (2020)

Yuying Liu Tianzhen Zhang Haizeng Zhang Jiping Li Nannan Zhou

Abstract Biomechanics is a fundamental feature of a cell. However, the manner by which actomysin tension affects tumor immune evasion remains unclear. Here we show that although cytotoxic T lymphocytes (CTL) can effectively destroy stiff differentiated tumor cells, they fail to kill soft tumor-repopulating cells (TRC). TRC softness prevented membrane pore formation caused by CTL-released perforin. Perforin interacting with nonmuscle myosin heavy-chain 9 transmitted forces to less F-actins in soft TRC, thus generating an inadequate contractile force for perforin pore formation. Stiffening TRC allowed perforin the ability to drill through the membrane, leading to CTL-mediated killing of TRC. Importantly, overcoming mechanical softness in human TRC also enhanced TRC cell death caused by human CTL, potentiating a mechanics-based immunotherapeutic strategy. These findings reveal a mechanics-mediated tumor immune evasion, thus potentially providing an alternative approach for tumor immunotherapy. Significance: Tumor-repopulating cells evade CD8+ cytolytic T-cell killing through a mechanical softness mechanism, underlying the impediment of perforin pore formation at the immune synapse site.

CTL*

Immunosurveillance

10.1158/0008-5472.can-20-2569

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Citations (81)