Fructose-1,6-bisphosphatase loss modulates STAT3-dependent expression of PD-L1 and cancer immunity

Wang, Bo; Zhou, Yingke; Zhang, Jun; Jin, Xin; Wu, Heshui; Huang, Haojie

doi:10.7150/thno.38137

Cited by 33 publications

(26 citation statements)

References 53 publications

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“…f TGM2 may regulate PD-L1 via NF-κB/STAT3 signaling pathways: a TGM2 activated AKT pathway and then promotes the activation of downstream transcription factor NF-κB which has been reported to be able to directly bind with the promoter of PD-L1 and stimulate its transcription. b TGM2 may promote the phosphorylation of STAT3 despite the underlying pathways remains unclear, and then p-STAT3 binds to the promoter of PD-L1 and stimulate its transcription are reported to be capable to regulate the expression of PD-L1 [19,20]. We knocked down TGM2 in PANC-1 and Mia PaCa-2 cells, a decreasing level of p-STAT3 was observed ( Fig.…”

Section: Tgm2 May Regulate Pd-l1 Expression Via Stat3/nf-κb Signalingmentioning

confidence: 92%

Immune subtyping for pancreatic cancer with implication in clinical outcomes and improving immunotherapy

Liu

Zhang

et al. 2021

Cancer Cell Int

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Background Emerging evidence has shown that intra-tumor immune features are associated with response to immune checkpoint blockade (ICB) therapy. Accordingly, patient stratification is needed for identifying target patients and designing strategies to improve the efficacy of ICB therapy. We aimed to depict the specific immune features of patients with pancreatic cancer and explore the implication of immune diversity in prognostic prediction and individualized immunotherapy. Methods From transcriptional profiles of 383 tumor samples in TCGA, ICGC, and GEO database, robust immune subtypes which had different response immunotherapy, including ICB therapy, were identified by consensus clustering with five gene modules. DEGs analysis and tumor microarray were used to screen and demonstrate potential targets for improving ICB therapy. Results Three subtypes of pancreatic cancer, namely cluster 1–3 (C1–C3), characterized with distinct immune features and prognosis, were generated. Of that, subtype C1 was an immune-cold type in lack of immune regulators, subtype C2, with an immunosuppression-dominated phenotype characterized by robust TGFβ signaling and stromal reaction, showed the worst prognosis, subtype C3 was an immune-hot type, with massive immune cell infiltration and in abundance of immune regulators. The disparity of immune features uncovered the discrepant applicability of anti-PD-1/PD-L1 therapy and potential sensitivity to other alternative immunotherapy for each subtype. Patients in C3 were more suitable for anti-PD-1/PD-L1 therapy, while patients in the other two clusters may need combined strategies targeted on other immune checkpoints or oncogenic pathways. A promising target for improving anti-PD-1/PD-L1 treatment, TGM2, was screened out and its role in the regulation of PD-L1 was investigated for the first time. Conclusion Collectively, immune features of pancreatic cancer contribute to distinct immunosuppressive mechanisms that are responsible for individualized immunotherapy. Despite pancreatic cancer being considered as a poor immunogenic cancer type, the derived immune subtypes may have implications in tailored designing of immunotherapy for the patients. TGM2 has potential synergistic roles with ICB therapy.

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Section: Tgm2 May Regulate Pd-l1 Expression Via Stat3/nf-κb Signalingmentioning

confidence: 92%

Immune subtyping for pancreatic cancer with implication in clinical outcomes and improving immunotherapy

Liu

Zhang

et al. 2021

Cancer Cell Int

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“…As a key regulator for multiple cellular processes including proliferation, differentiation, immune function and angiogenesis, STAT3 activation has been implicated as a critical mechanism in drug resistance for a range of oncogene driven cancers in targeted therapeutics. Activated STAT3 also plays an important role in immune response through regulation of immune checkpoint proteins and tumor environment cytokines 46 , 47 . Therefore, targeting STAT3 has a wide range of therapeutic implications.…”

Section: Discussionmentioning

confidence: 99%

A novel STAT3 inhibitor W2014-S regresses human non-small cell lung cancer xenografts and sensitizes EGFR-TKI acquired resistance

Zheng¹,

Dong²,

Mo³

et al. 2021

Theranostics

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Constitutive activation of signal transducer and activator of transcription 3 (STAT3) is a common feature in human non-small cell lung cancer (NSCLC). STAT3 plays an important role in cancer progression as a driver oncogene and acquired resistance of targeted therapies as an alternatively activated pathway. W2014-S with pharmacophore structure of imidazopyridine, which was firstly reported to be utilized in STAT3 inhibitor discovery, was screened out as a potent STAT3 inhibitor from a library of small molecules. The aim of this study is to investigate the antitumor activities and mechanisms of W2014-S in NSCLC and effect on epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) resistance in vitro and in vivo . Methods: SPR analysis, Co-immunoprecipitation, confocal microscope imaging, and luciferase report gene assays were utilized to determine the mechanisms. Cell viability, colonial survival, wound healing, cell invasion assay, human cancer cell xenografts and PDX tumor xenografts were used to determine antitumor activities. Results: W2014-S disrupted STAT3 dimerization and selectively inhibited aberrant STAT3 signaling in NSCLC cell line. W2014-S strongly suppressed proliferation, survival, migration and invasion of lung cancer cells with aberrant STAT3 activation and inhibited the growth of human NSCLC cell xenografts and PDX tumor xenografts in mouse model. Furthermore, W2014-S significantly sensitized resistant NSCLC cell line to gefitinib and erlotinib in vitro and enhances the anti-tumor effect of gefitinib in TKI-resistant lung cancer xenografts in vivo . Conclusions: Our study has provided a novel STAT3 inhibitor with significant anti-tumor activities in NSCLC and suggests that combination of STAT3 inhibitor such as W2014-S with gefitinib could serve as a promising strategy to overcome EGFR-TKIs acquired resistance in NSCLC patients.

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“…However, the non-canonical functions of FBP1 are independent of its enzymatic activity. For example, noncanonical FBP1 acts as a co-suppressor for many transcriptional factors, including HIF-1α 5 , β-catenin 35 , NOTCH1 11 , STAT3 36 and c-MYC 10 , and it also regulates their functions through direct interactions, possibly leading to protein degradation. In addition, FBP1 binds to the WW domain of IQGAP1, and impedes IQGAP1-dependent ERK1/2 phosphorylation independent of FBP1 enzymatic activity 37 .…”

Section: Discussionmentioning

confidence: 99%

“…A recent study revealed a new tumor suppressor function of FBP1 to inhibit PD-L1 expression and enhance cancer immunity 36 . They found that FBP1 inhibits STAT3-dependent PD-L1 transcription, a finding that is consistent with our discovery in breast cancer.…”

Section: Discussionmentioning

confidence: 99%

Fructose-1, 6-bisphosphatase 1 interacts with NF-κB p65 to regulate breast tumorigenesis via PIM2 induced phosphorylation

Lü¹,

Ren²,

Yang³

et al. 2020

Theranostics

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Rationale: Fructose-1, 6-bisphosphatase 1 (FBP1), a rate-limiting enzyme in gluconeogenesis, was recently shown to be a tumor suppressor and could mediate the activities of multiple transcriptional factors via its non-canonical functions. However, the underlying mechanism of posttranscriptional modification on the non-canonical functions of FBP1 remains elusive. Methods: We employed immunoaffinity purification to identify binding partner(s) and used co-immunoprecipitation to verify their interactions. Kinase reaction was used to confirm PIM2 could phosphorylate FBP1. Overexpression or knockdown proteins were used to assess the role in modulating p65 protein stability. Mechanistic analysis was involved in protein degradation and polyubiquitination assays. Nude mice and PIM2-knockout mice was used to study protein functions in vitro and in vivo . Results: Here, we identified Proviral Insertion in Murine Lymphomas 2 (PIM2) as a new binding partner of FBP1, which could phosphorylate FBP1 on Ser144. Surprisingly, phosphorylated FBP1 Ser144 abrogated its interaction with NF-κB p65, promoting its protein stability through the CHIP-mediated proteasome pathway. Furthermore, phosphorylation of FBP1 on Ser144 increased p65 regulated PD-L1 expression. As a result, phosphorylation of FBP1 on Ser144 promoted breast tumor growth in vitro and in vivo . Moreover, the levels of PIM2 and pSer144-FBP1 proteins were positively correlated with each other in human breast cancer and PIM2 knockout mice. Conclusions: Our findings revealed that phosphorylation noncanonical FBP1 by PIM2 was a novel regulator of NF-κB pathway, and highlights PIM2 inhibitors as breast cancer therapeutics.

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Fructose-1,6-bisphosphatase loss modulates STAT3-dependent expression of PD-L1 and cancer immunity

Cited by 33 publications

References 53 publications

Immune subtyping for pancreatic cancer with implication in clinical outcomes and improving immunotherapy

Immune subtyping for pancreatic cancer with implication in clinical outcomes and improving immunotherapy

A novel STAT3 inhibitor W2014-S regresses human non-small cell lung cancer xenografts and sensitizes EGFR-TKI acquired resistance

Fructose-1, 6-bisphosphatase 1 interacts with NF-κB p65 to regulate breast tumorigenesis via PIM2 induced phosphorylation

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