cIAP1/TRAF2 interplay promotes tumor growth through the activation of STAT3

Dumetier, Baptiste; Zadoroznyj, Aymeric; Berthelet, Jean; Causse, Sébastien; Allègre, Julien; Bourgeois, Pauline; Cattin, Florine; Racoeur, Cindy; Paul, Catherine; Garrido, Carmen; Dubrez, Laurence

doi:10.1038/s41388-022-02544-y

Cited by 4 publications

(4 citation statements)

References 50 publications

(70 reference statements)

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“…Combined with the above results and those supported by other studies [ 27 , 28 ], we come to conclude that STAT3 blockade could be a promising therapeutic strategy for HNSCC. Phosphorylation and transactivation of STAT3 induced by cytokines and non-receptor tyrosine kinase are disrupted by TPCA-1 in dose- and time-dependent manner [ 29 ].…”

Section: Discussionsupporting

confidence: 84%

IL-8 activates fibroblasts to promote the invasion of HNSCC cells via STAT3-MMP1

Chen,

Huang,

Gan

et al. 2024

Cell Death Discov.

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Matrix metalloproteinase-1 (MMP1) has an aberrant expression relevant to various behaviors of cancers. As dominant components of the tumor stroma, fibroblasts constitute an important source of Matrix metalloproteinase (MMPs) including mainly MMP1. The impacts of MMP1 derived from fibroblasts in tumor microenvironment, however, is not well defined. In this study, we demonstrated a part of crosstalk between fibroblasts and cancer cells that enhanced the invasiveness of cancer cells, IL8-induced activation of STAT3 signaling pathway as a key promoter to elevated MMP1 level in fibroblasts that supports the migration and invasion of head and neck squamous cell carcinoma (HNSCC) cells by extracellular matrix degradation. Importantly, once exposed to the inhibitor of STAT3 phosphorylation (TPCA-1), the enhanced induction of HNSCC cells invasion triggered by fibroblasts was significantly impaired.

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Section: Discussionsupporting

confidence: 84%

IL-8 activates fibroblasts to promote the invasion of HNSCC cells via STAT3-MMP1

Chen,

Huang,

Gan

et al. 2024

Cell Death Discov.

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“…Knockdown of BIRC2 inhibited the proliferative ability of HCC cells and activated the apoptosis of HCC cells. These results suggest that BIRC2 plays a pro-carcinogenic role in HCC, which is consistent with its role in other tumours [ 55 , 56 ]. Interestingly, our experimental results revealed that altered BIRC2 expression could affect the expression of the downstream proteins Cleaved caspase9 and Cleaved caspase7, but had no significant effect on the expression of Bax and Cyt-c proteins.…”

Section: Discussionsupporting

confidence: 82%

NAP1L1 regulates BIRC2 ubiquitination modification via E3 ubiquitin ligase UBR4 and hence determines hepatocellular carcinoma progression

Zhang,

et al. 2024

Cell Death Discov.

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We have previously shown that nucleosome assembly protein 1-like 1 (NAP1L1) plays an important role in the abnormal proliferation of hepatocellular carcinoma (HCC) cells. However, the effects of NAP1L1 on the malignant behaviour of HCC cells, including cell migration, invasion and apoptosis, remain unclear. Baculoviral IAP repeat-containing 2 (BIRC2) plays a key role in initiating the abnormal proliferation, apoptotic escape and multidrug resistance of HCC cells; however, the mechanisms through which its stability is regulated in HCC remain elusive. Here, we found that knockdown of NAP1L1 inhibited the proliferation of HCC cells and activated apoptotic pathways but did not remarkably affect the migratory and invasive abilities of HCC cells. In addition, knockdown of NAP1L1 did not alter the expression of BIRC2 at the transcriptional level but substantially reduced its expression at the translational level, suggesting that NAP1L1 is involved in the post-translational modification (such as ubiquitination) of BIRC2. Furthermore, BIRC2 was highly expressed in human HCC tissues and promoted the proliferation and apoptotic escape of HCC cells. Co-immunoprecipitation (Co-IP) assay and mass spectrometry revealed that NAP1L1 and BIRC2 did not bind to each other; however, ubiquitin protein ligase E3 component n-recognin 4 (UBR4) was identified as an intermediate molecule associating NAP1L1 with BIRC2. Knockdown of NAP1L1 promoted the ubiquitin-mediated degradation of BIRC2 through the ubiquitin–protein junction of UBR4, which in turn inhibited the proliferation and apoptotic escape of HCC cells and exerted anti-tumour effects. In conclusion, this study reveals a novel mechanism through which NAP1L1 regulates the ubiquitination of BIRC2 through UBR4, thereby determining the progression of HCC. Based on this mechanism, suppression of NAP1L1 may inhibit tumour progression in patients with HCC with high protein expression of NAP1L1 or BIRC2.

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“…Activation of NF-κβ also induces the expression of pro-inflammatory cytokines, including TNF-α and IL-6, which are required for STAT3 activation. This suggests that the crosstalk between NF-κβ and STAT3 signalling pathways drive cancer progression [ 28 , 29 , 48 , 49 ]. Additionally, treatment with LCL161 can induce a robust inflammatory response via activation of macrophages and dendritic cells, which triggers the release of pro-inflammatory cytokines, including TNF-α and IL-6 [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

Combination of bazedoxifene with chemotherapy and SMAC-mimetics for the treatment of colorectal cancer

Dmello,

Palmieri,

Thilakasiri

et al. 2024

Cell Death Dis

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Excessive STAT3 signalling via gp130, the shared receptor subunit for IL-6 and IL-11, contributes to disease progression and poor survival outcomes in patients with colorectal cancer. Here, we provide evidence that bazedoxifene inhibits tumour growth via direct interaction with the gp130 receptor to suppress IL-6 and IL-11-mediated STAT3 signalling. Additionally, bazedoxifene combined with chemotherapy synergistically reduced cell proliferation and induced apoptosis in patient-derived colon cancer organoids. We elucidated that the primary mechanism of anti-tumour activity conferred by bazedoxifene treatment occurs via pro-apoptotic responses in tumour cells. Co-treatment with bazedoxifene and the SMAC-mimetics, LCL161 or Birinapant, that target the IAP family of proteins, demonstrated increased apoptosis and reduced proliferation in colorectal cancer cells. Our findings provide evidence that bazedoxifene treatment could be combined with SMAC-mimetics and chemotherapy to enhance tumour cell apoptosis in colorectal cancer, where gp130 receptor signalling promotes tumour growth and progression.

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cIAP1/TRAF2 interplay promotes tumor growth through the activation of STAT3

Cited by 4 publications

References 50 publications

IL-8 activates fibroblasts to promote the invasion of HNSCC cells via STAT3-MMP1

IL-8 activates fibroblasts to promote the invasion of HNSCC cells via STAT3-MMP1

NAP1L1 regulates BIRC2 ubiquitination modification via E3 ubiquitin ligase UBR4 and hence determines hepatocellular carcinoma progression

Combination of bazedoxifene with chemotherapy and SMAC-mimetics for the treatment of colorectal cancer

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