A circular network of coregulated sphingolipids dictates lung cancer growth and progression

Meng, Qiong; Hu, Xueqiang; Zhao, Xu; Kong, Xiangbin; Meng, Ya-Ming; Chen, Yitian; Su, Lili; Jiang, Xue; Qiu, Xiaoyi; Huang, Cheng; Liu, Chao; Wang, Minghui; Wong, Ping-Pui

doi:10.1016/j.ebiom.2021.103301

Cited by 28 publications

(20 citation statements)

References 45 publications

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“…Mechanistically, our proteomic analysis reveals a consistent up-regulation of sphingolipid metabolic enzyme ASAH2 and β5-integrin expression in GemR pancreatic and lung cancer cells as well as stable β5-integrin–expressing cells. We and others have shown that sphingolipid metabolic reprogramming can promote cancer growth and progression as well as antitumor immune response ( 21 , 33 ), whereas our current study shows that β5-integrin regulates ASAH2 expression through the Src-STAT3 signaling axis. ASAH2 is known as a ceramidase, which has been shown to regulate intracellular ceramide concentrations ( 26 ), whereas ceramide plays a key role in many cellular processes including cell survival and death ( 33 ).…”

Section: Discussioncontrasting

confidence: 68%

“…Integrin is known to play an important regulatory role in the focal adhesion pathway and actin cytoskeleton arrangement ( 29 ). For other pathways, we and others have shown that sphingolipid metabolic reprogramming is linked to cancer progression ( 21 , 27 ), whereas its roles in β5-integrin–mediated pyroptosis and chemoresistance remain unknown. We therefore performed RT-PCR analysis on the expression of sphingolipid metabolic genes based on the sphingolipid signaling pathway, particularly focusing on ceramide metabolism in four different WT or GemR cell lines and ctrl or stable β5-integrin–expressing cell lines, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…Emerging evidence suggests that sphingolipid metabolism is among the top dysregulated pathways in cancer ( 20 , 21 ). In general, sphingolipids are shown to be important in maintaining cell membrane integrity and intracellular signaling activity ( 22 ).…”

Section: Introductionmentioning

confidence: 99%

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Targeting Src reactivates pyroptosis to reverse chemoresistance in lung and pancreatic cancer models

Chen

Huang

et al. 2023

Sci. Transl. Med.

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Pancreatic and lung cancers frequently develop resistance to chemotherapy-induced cell apoptosis during the treatment, indicating that targeting nonapoptotic-related pathways, such as pyroptosis, can be an alternative cancer treatment strategy. Pyroptosis is a gasdermin-driven lytic programmed cell death triggered by inflammatory caspases when initiated by canonical or noncanonical pathways that has been recently seen as a potential therapeutic target in cancer treatment. However, overcoming chemoresistance in cancers by modulating pyroptosis has not been explored. Here, we demonstrate that β5-integrin represses chemotherapy-induced canonical pyroptosis to confer cancer chemoresistance through ASAH2-driven sphingolipid metabolic reprogramming. Clinically, high β5-integrin expression associates with poor patient prognosis and chemotherapeutic responses in cancers. In addition, chemoresistant cells in vitro fail to undergo chemotherapy-induced pyroptosis, which is controlled by β5-integrin. Mechanistically, proteomic and lipidomic analyses indicate that β5-integrin up-regulates sphingolipid metabolic enzyme ceramidase (ASAH2) expression through Src–signal transducer and activator of transcription 3 (STAT3) signaling, which then reduces the metabolite ceramide concentration and subsequent ROS production to prohibit chemotherapy-induced canonical pyroptosis. Using cancer cell lines, patient-derived tumor organoids, and orthotopic lung and pancreatic animal models, we show that administration of a Src or ceramidase inhibitor rescues the response of chemoresistant pancreatic and lung cancer cells to chemotherapy by reactivating pyroptosis in vitro and in vivo. Overall, our results suggest that pyroptosis-based therapy is a means to improve cancer treatment and warrants further investigation.

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Section: Discussioncontrasting

confidence: 68%

Section: Resultsmentioning

confidence: 99%

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Targeting Src reactivates pyroptosis to reverse chemoresistance in lung and pancreatic cancer models

Chen

Huang

et al. 2023

Sci. Transl. Med.

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“…In this context, estradiol down regulated: ZFYVE16, a FYVE zink finger family protein (also called endofin) that regulates cell adhesion and induces cell migration [ 46 ] by regulating TGFβ signaling pathway and is downregulated by ER-β in cancer cells [ 47 ]; and epiregulin, which stimulates cell migration via MAPK activation [ 57 ]. Additionally, estradiol downregulated multiple other genes known to induce cell migration, i.e., B3GNT5, a sphingolipid metabolic enzyme [ 58 ]; FADS1 [ 44 ], MIR1908 (a cholesterol responsive miRNA [ 45 ]); nucleoporin 58 kDa (NUP58) [ 55 ]; TOPORS [ 53 , 54 ]; Six homeobox 4 [ 48 ]; Retinoblastoma binding protein-9 (RBBP9) [ 49 ].…”

Section: Discussionmentioning

confidence: 99%

Estradiol Inhibits Human Brain Vascular Pericyte Migration Activity: A Functional and Transcriptomic Analysis

Kurmann

Okoniewski

Dubey

2021

Cells

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Stroke is the third leading cause of mortality in women and it kills twice as many women as breast cancer. A key role in the pathophysiology of stroke plays the disruption of the blood–brain barrier (BBB) within the neurovascular unit. While estrogen induces vascular protective actions, its influence on stroke remains unclear. Moreover, experiments assessing its impact on endothelial cells to induce barrier integrity are non-conclusive. Since pericytes play an active role in regulating BBB integrity and function, we hypothesize that estradiol may influence BBB by regulating their activity. In this study using human brain vascular pericytes (HBVPs) we investigated the impact of estradiol on key pericyte functions known to influence BBB integrity. HBVPs expressed estrogen receptors (ER-α, ER-β and GPER) and treatment with estradiol (10 nM) inhibited basal cell migration but not proliferation. Since pericyte migration is a hallmark for BBB disruption following injury, infection and inflammation, we investigated the effects of estradiol on TNFα-induced PC migration. Importantly, estradiol prevented TNFα-induced pericyte migration and this effect was mimicked by PPT (ER-α agonist) and DPN (ER-β agonist), but not by G1 (GPR30 agonist). The modulatory effects of estradiol were abrogated by MPP and PHTPP, selective ER-α and ER-β antagonists, respectively, confirming the role of ER-α and ER-β in mediating the anti-migratory actions of estrogen. To delineate the intracellular mechanisms mediating the inhibitory actions of estradiol on PC migration, we investigated the role of AKT and MAPK activation. While estradiol consistently reduced the TNFα-induced MAPK and Akt phosphorylation, only the inhibition of MAPK, but not Akt, significantly abrogated the migratory actions of TNFα. In transendothelial electrical resistance measurements, estradiol induced barrier function (TEER) in human brain microvascular endothelial cells co-cultured with pericytes, but not in HBMECs cultured alone. Importantly, transcriptomics analysis of genes modulated by estradiol in pericytes showed downregulation of genes known to increase cell migration and upregulation of genes known to inhibit cell migration. Taken together, our findings provide the first evidence that estradiol modulates pericyte activity and thereby improves endothelial integrity.

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“…A population-based cohort nested case-control study showed that geometric mean concentrations of plasma S1P and total ceramide were higher in lung cancer patients than in controls, suggesting these as potential markers of latent lung cancer [ 53 ]. Meng et al [ 54 ] analyzed the RNA-seq datasets obtained from TCGA, GEO, and Hou lung and found a consistent alteration of 15 sphingolipid metabolic gene expression in NSCLC patient tissues as compared to the normal lung tissues. Among these genes, the expression of B3GNT5 and GAL3ST1 is most significantly associated with patient prognosis and their metabolites are potential biomarkers for staging patients.…”

Section: Sphingolipid Metabolism and Lung Cancer Treatmentmentioning

confidence: 99%

Sphingolipid Metabolism and Signaling in Lung Cancer: A Potential Therapeutic Target

Lin

Wang

et al. 2022

Journal of Oncology

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Sphingolipids are important bioactive lipids that not only play an important role in maintaining the barrier function and fluidity of cell membranes but also regulate multiple processes in cancer development by controlling multiple signaling pathways in the signal transduction network. Dysregulation of sphingolipid metabolism is thought to be one of the most important dysregulated pathways in lung cancer, the most prevalent type of cancer in terms of incidence and mortality worldwide. This article focuses on lung cancer, reviewing the important lipids in sphingolipid metabolism and the related enzymes in relation to lung cancer progression and their effects on the tumor microenvironment and discussing their roles in the diagnosis and treatment of lung cancer.

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A circular network of coregulated sphingolipids dictates lung cancer growth and progression

Cited by 28 publications

References 45 publications

Targeting Src reactivates pyroptosis to reverse chemoresistance in lung and pancreatic cancer models

Targeting Src reactivates pyroptosis to reverse chemoresistance in lung and pancreatic cancer models

Estradiol Inhibits Human Brain Vascular Pericyte Migration Activity: A Functional and Transcriptomic Analysis

Sphingolipid Metabolism and Signaling in Lung Cancer: A Potential Therapeutic Target

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