CPT1A promotes anoikis resistance in esophageal squamous cell carcinoma via redox homeostasis

Tian, Tian; Lu, Yong; Lin, Jin-Fei; Chen, Miao; Qiu, Huijuan; Zhu, Weishan; Sun, Haohui; Huang, Jinsheng; Han, Yu; Deng, Wuguo

doi:10.1016/j.redox.2022.102544

Cited by 27 publications

(15 citation statements)

References 33 publications

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“…Despite the lack of consensus, tumors are well known as heterogeneous entities consisting of cancer cells with varying metabolic states. It is also well recognized that cancer cells can optimize the exploitation of limited energy resources (40), particularly when cells undergo ECM detachment.…”

Section: Discussionmentioning

confidence: 99%

Detachment-activated FAK-STAT3-NNMT inhibits anoikis by enhancing fatty acid oxidation in breast cancer

Tong,

Ma,

Gao

et al. 2024

Preprint

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Purpose: Breast cancer metastasis claims the majority of breast cancer-related deaths. Anoikis resistance is a key prerequisite for tumor metastasis. Possible mechanism of evading anoikis in breast cancer remains unclear. Our previous research demonstrated that Nicotinamide N-methyltransferase (NNMT) has essential functions in cancer development and metastasis. However, the spercific functional mechanisms of NNMT in breast cancer anoikisp remain to be explored Method: Immunofluorescence staining, confocal microscopy analysis, immunoblotting and qPCR were used to analyze NNMT expression. Flow cytometry and soft agar assay were used to analyze the proportion of breast cancer cells undergoing anoikis. ChIP assay and detached cell model were used to confirm the presence of FAK-STAT3-NNMT in detached breast cancer cells. BODIPY staining was used to visualize lipid deposit in the cytoplasm, and Seahorse analysis was used to directly measure FAO rate of attached and detached breast cancer cells. Results: Detachment of breast cancer cells activates the FAK-STAT3 axis to increase the transcription of NNMT, which then protects breast cancer cells from anoikis by enhancing fatty acid oxidation (FAO). Mechanistically, NNMT promotes the expression of CPT1A, a FAO rate-limiting gene, by suppressing PP2A methylation. Furthermore, NNMT-induced FAO accelerates the clearance of reactive oxygen species (ROS), which triggers anoikis and hinders cancer metastasis, by maintaining NADP+/NADPH balance. In vivo experiments show that NNMT-knockdown breast cancer cells colonize the lung much less than that of NNMT high expression cells. Additionally, inhibitors of NNMT or FAO suppressed breast cancer cell metastasis, suggesting that NNMT-mediated FAO enhances the metastatic potential of breast cancer. Conclusion: Our study identifies that NNMT, an enzyme upregulated during detachment via the FAK-STAT3 axis, activates the FAO pathway to resist anoikis of breast cancer cells.

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Section: Discussionmentioning

confidence: 99%

Detachment-activated FAK-STAT3-NNMT inhibits anoikis by enhancing fatty acid oxidation in breast cancer

Tong,

Ma,

Gao

et al. 2024

Preprint

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“… 28 Disruption of CPT1A through genetic or pharmacologic ways can cut off the supply of NADPH, thus preventing anchor-independent growth of ESCC cells and lung metastasis. 29 Recently, CPT1A was identified as a succinyltransferase. Succinylation has gained increasing attention in recent years because succinylation modification is relatively conserved and is involved in almost all biological processes.…”

Section: Discussionmentioning

confidence: 99%

CPT1A mediates the succinylation of SP5 which activates transcription of PDPK1 to promote the viability and glycolysis of prostate cancer cells

Liu,

Chen,

Zhang

et al. 2024

Cancer Biology & Therapy

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Succinylation modification involves in the progression of human cancers. The present study aimed to investigate the role of CPT1A, which is a succinyltransferase in the progression of prostate cancer (PCa). CCK-8 was used to detect the cell viability. Seahorse was performed to evaluate the cell glycolysis. Luciferase assay was used to detect the transcriptional regulation. ChIP was performed to assess the binding between transcriptional factors with the promoters. Co-IP was used to assess the binding between proteins. We found that CPT1A was highly expressed in PCa tissues and cell lines. Silencing of CPT1A inhibited the viability and glycolysis of PCa cells. Mechanistically, CPT1A promoted the succinylation of SP5, which strengthened the binding between SP5 and the promoter of PDPK1. SP5 activated PDPK1 transcription and PDPK1 activated the AKT/mTOR signal pathway. These findings might provide novel targets for the diagnosis or therapy of prostate cancer.

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“…Moreover, the substantial lactate produced via the glycolytic pathway contributes to tumor microenvironment acidification, promoting angiogenesis and the renewal of tumor stemness ( 48 , 49 ). Recent studies have also highlighted enhanced lipid metabolism as a distinct metabolic feature in some tumors ( 11 , 50 , 51 ). For instance, the depletion of LPCAT1, which is responsible for cholesterol synthesis, has been proven to inhibit anchorage-independent growth in esophageal squamous cell carcinoma cells ( 52 ).…”

Section: Discussionmentioning

confidence: 99%

“…However, to accomplish eventual colonization in distant organs, the cells’ fate in circulation is particularly important. Anoikis is defined as the apoptosis that occurs when cells detach from the surrounding extracellular matrix (ECM) ( 11 - 14 ). After detaching from the primary lesions, the majority of tumor cells are eliminated through this process; however, a small subset of cancer cells reprogram intracellular and extracellular signals to survive in lymphatic and blood vessels ( 15 , 16 ).…”

Section: Introductionmentioning

confidence: 99%

ENO2 promotes anoikis resistance in anaplastic thyroid cancer by maintaining redox homeostasis

Zhang,

Ji,

Wang

2024

Gland Surg

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Background Anoikis presents a significant barrier in the metastasis of cancer. As the most aggressive type of thyroid cancer, anaplastic thyroid cancer (ATC) exhibits a high risk of metastasis and is characterized by high mortality. Therefore, investigating the molecular mechanisms of anoikis resistance in ATC is important for devising therapeutic targets in clinical research. Methods Differentially Expressed Genes were screened in ATC cells under attached and detached culture conditions with RNA-seq. Investigate the impact of enolase 2 (ENO2) on apoptosis and spheroid formation by gain and loss of function. Changes of reactive oxygen species (ROS), glutathione (GSH) and nicotinamide adenine dinucleotide phosphate (NADPH) were detected to assess redox balance. The transcriptional regulatory role of signal transducer and activator of transcription 1 (STAT1) on ENO2 was validated through Dual-Luciferase Reporter Gene Assay. Explore the impact of ENO2 expression on the formation of lung metastases in nude mice. Results We found that the glycolysis process was activated in detached ATC cells. Several genes in the glycolysis process, particularly ENO2 , a member of the enolase superfamily was upregulated in ATC cells cultured in suspension. The upregulation of ENO2 enabled the maintenance of redox balance by supplying GSH and NADPH, thereby preventing cells from undergoing anoikis. In terms of mechanism, the expression of STAT1 was enhanced in anoikis resistance cells, which in turn positively regulated the expression of ENO2. In vivo , ENO2-suppressed ATC cells resulted in a significantly lower rate of lung colonization compared to control ATC cells. Conclusions Stable expression of ENO2 and the maintenance of redox balance played a pivotal role in facilitating anoikis resistance of ATC.

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CPT1A promotes anoikis resistance in esophageal squamous cell carcinoma via redox homeostasis

Cited by 27 publications

References 33 publications

Detachment-activated FAK-STAT3-NNMT inhibits anoikis by enhancing fatty acid oxidation in breast cancer

Detachment-activated FAK-STAT3-NNMT inhibits anoikis by enhancing fatty acid oxidation in breast cancer

CPT1A mediates the succinylation of SP5 which activates transcription of PDPK1 to promote the viability and glycolysis of prostate cancer cells

ENO2 promotes anoikis resistance in anaplastic thyroid cancer by maintaining redox homeostasis

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