The Prognostic, Diagnostic, and Therapeutic Potential of TRAIL Signalling in Cardiovascular Diseases

Kelland, Elaina; Patil, Manisha S.; Patel, Sanjay; Cartland, Siân P.; Kavurma, Mary M.

doi:10.3390/ijms24076725

Cited by 6 publications

(4 citation statements)

References 103 publications

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“…Although TRAIL induces selective apoptosis in cancer cells, the clinical application of TRAIL has been rather limited [ 26 – 28 ]. Exploring suitable biomarkers for the selection of patients responsive to TRAIL is pivotal for devising rational individualized therapy regimens.…”

Section: Discussionmentioning

confidence: 99%

Cytoplasmic TP53INP2 acts as an apoptosis partner in TRAIL treatment: the synergistic effect of TRAIL with venetoclax in TP53INP2-positive acute myeloid leukemia

Ren,

Huang,

Yang

et al. 2024

J Exp Clin Cancer Res

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Background Acute myeloid leukemia (AML) is a hematopoietic malignancy with poor outcomes, especially in older AML patients. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is considered a promising anticancer drug because it selectively induces the extrinsic apoptosis of tumor cells without affecting normal cells. However, clinical trials have shown that the responses of patients to TRAIL are significantly heterogeneous. It is necessary to explore predictable biomarkers for the preselection of AML patients with better responsiveness to TRAIL. Here, we investigated the critical role of tumor protein p53 inducible nuclear protein 2 (TP53INP2) in the AML cell response to TRAIL treatment. Methods First, the relationship between TP53INP2 and the sensitivity of AML cells to TRAIL was determined by bioinformatics analysis of Cancer Cell Line Encyclopedia datasets, Cell Counting Kit-8 assays, flow cytometry (FCM) and cell line-derived xenograft (CDX) mouse models. Second, the mechanisms by which TP53INP2 participates in the response to TRAIL were analyzed by Western blot, ubiquitination, coimmunoprecipitation and immunofluorescence assays. Finally, the effect of TRAIL alone or in combination with the BCL-2 inhibitor venetoclax (VEN) on cell survival was explored using colony formation and FCM assays, and the effect on leukemogenesis was further investigated in a patient-derived xenograft (PDX) mouse model. Results AML cells with high TP53INP2 expression were more sensitive to TRAIL in vitro and in vivo. Gain- and loss-of-function studies demonstrated that TP53INP2 significantly enhanced TRAIL-induced apoptosis, especially in AML cells with nucleophosmin 1 (NPM1) mutations. Mechanistically, cytoplasmic TP53INP2 maintained by mutant NPM1 functions as a scaffold bridging the ubiquitin ligase TRAF6 to caspase-8 (CASP 8), thereby promoting the ubiquitination and activation of the CASP 8 pathway. More importantly, simultaneously stimulating extrinsic and intrinsic apoptosis signaling pathways with TRAIL and VEN showed strong synergistic antileukemic activity in AML cells with high levels of TP53INP2. Conclusion Our findings revealed that TP53INP2 is a predictor of responsiveness to TRAIL treatment and supported a potentially individualized therapeutic strategy for TP53INP2-positive AML patients.

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Section: Discussionmentioning

confidence: 99%

Cytoplasmic TP53INP2 acts as an apoptosis partner in TRAIL treatment: the synergistic effect of TRAIL with venetoclax in TP53INP2-positive acute myeloid leukemia

Ren,

Huang,

Yang

et al. 2024

J Exp Clin Cancer Res

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“…Yet, a tremendous amount of work also suggests that TRAIL and its receptors are likely to play a role in several human diseases including, but not limited to, obesity and diabetes [ 274 ], and are associated with inflammation [ 2 , 117 , 275 ], neurological disorders [ 276 ] and cardiac diseases [ 277 ].…”

Section: Physiological and Physiopathological Functions Of Trailmentioning

confidence: 99%

TNF-Related Apoptosis-Inducing Ligand: Non-Apoptotic Signalling

Guerrache,

Micheau

2024

Cells

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TNF-related apoptosis-inducing ligand (TRAIL or Apo2 or TNFSF10) belongs to the TNF superfamily. When bound to its agonistic receptors, TRAIL can induce apoptosis in tumour cells, while sparing healthy cells. Over the last three decades, this tumour selectivity has prompted many studies aiming at evaluating the anti-tumoral potential of TRAIL or its derivatives. Although most of these attempts have failed, so far, novel formulations are still being evaluated. However, emerging evidence indicates that TRAIL can also trigger a non-canonical signal transduction pathway that is likely to be detrimental for its use in oncology. Likewise, an increasing number of studies suggest that in some circumstances TRAIL can induce, via Death receptor 5 (DR5), tumour cell motility, potentially leading to and contributing to tumour metastasis. While the pro-apoptotic signal transduction machinery of TRAIL is well known from a mechanistic point of view, that of the non-canonical pathway is less understood. In this study, we the current state of knowledge of TRAIL non-canonical signalling.

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“…Yet, a tremendous amount of work also suggests that TRAIL and its receptors are likely to play a role in several human diseases including, but not limited to, obesity and diabetes [274], and are associated with inflammation [2,117,275], neurological disorders [276] and cardiac diseases [277].…”

Section: Physiological and Physiopathological Functions Of Trailmentioning

confidence: 99%

TRAIL-Non-Apoptotic Signalling

Guerrache,

Micheau

2024

Preprint

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TNF-related apoptosis-inducing ligand (TRAIL or Apo2 or TNFSF10) belongs to the TNF superfamily. When bound to its agonistic receptors, TRAIL can induce apoptosis in tumour cells, while sparing healthy cells. This tumour selectivity prompted, over the last three decades, many studies aiming at evaluating the anti-tumoral potential of TRAIL or its derivatives. Although most of these attempts have failed, so far, novel formulations are still being evaluated. Yet, emerging evidence indicates that TRAIL can also trigger, on the other hand, a non-canonical signal transduction pathway that is likely to be detrimental for its use in oncology. Likewise, increasing studies suggest that TRAIL can induce, through Death receptor 5 (DR5) in some circumstances, tumour cell motility, potentially leading to and contributing to tumour metastasis. While the pro-apoptotic signal transduction machinery of TRAIL is well known from a mechanistic point of view, that of the non-canonical pathway is less understood. We are reviewing here the current state of knowledge of TRAIL non-canonical signalling.

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The Prognostic, Diagnostic, and Therapeutic Potential of TRAIL Signalling in Cardiovascular Diseases

Cited by 6 publications

References 103 publications

Cytoplasmic TP53INP2 acts as an apoptosis partner in TRAIL treatment: the synergistic effect of TRAIL with venetoclax in TP53INP2-positive acute myeloid leukemia

Cytoplasmic TP53INP2 acts as an apoptosis partner in TRAIL treatment: the synergistic effect of TRAIL with venetoclax in TP53INP2-positive acute myeloid leukemia

TNF-Related Apoptosis-Inducing Ligand: Non-Apoptotic Signalling

TRAIL-Non-Apoptotic Signalling

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