Induction of IRAK-M in melanoma induces caspase-3 dependent apoptosis by reducing TRAF6 and calpastatin levels

Geng, Degui; Ciavattone, Nicholas; Lasola, Jackline Joy; Shrestha, Rojesh; Sánchez, Amelia; Guo, James C. Y.; Vlk, Alexandra; Younis, Rania H.; Wang, Lucy; Brown, Alex J.; Zhang, Yuji; Velasco‐Gonzalez, Cruz; Tan, Aik Choon; Dávila, Eduardo

doi:10.1038/s42003-020-1033-y

Cited by 4 publications

(2 citation statements)

References 24 publications

(31 reference statements)

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“…Constitutive activation of known oncogenic signaling cascades including MAPK and NF-κB is a direct consequence of aberrant MyD88 and IRAK-4, creating an ideal environment for tumor initiation and progression across numerous malignancies beyond lymphoma (27)(28)(29)(30). Studies in human melanoma have shown that IRAK-4 is upregulated and activated in most cutaneous tumor samples (31,32).…”

Section: Introductionmentioning

confidence: 99%

Oral IRAK-4 Inhibitor CA-4948 Is Blood-Brain Barrier Penetrant and Has Single-Agent Activity against CNS Lymphoma and Melanoma Brain Metastases

Roemeling

Doonan

Klippel

et al. 2023

Clinical Cancer Research

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Purpose: An ongoing challenge in cancer is the management of primary and metastatic brain malignancies. This is partly due to restrictions of the blood-brain barrier (BBB) and their unique microenvironment. These challenges are most evident in cancers such as lymphoma and melanoma, which are typically responsive to treatment in systemic locations but resistant when established in the brain. We propose IRAK-4 as a potential target across these diseases and describe the activity and mechanism of oral IRAK-4 inhibitor CA-4948. Experimental Design: Human primary central nervous system lymphoma (PCNSL) and melanoma brain metastases (MBM) samples were analyzed for expression of IRAK-4 and downstream transcription pathways. We next determined the CNS applicability of CA-4948 in naïve and tumor-bearing mice using models of PCNSL and MBM. The mechanistic effect on tumors and the tumor microenvironment was then analyzed. Results: Human PCNSL and MBM have high expression of IRAK-4, IRAK-1, and NF-κB. This increase in inflammation results in reflexive inhibitory signaling. Similar profiles are observed in immunocompetent murine models. Treatment of tumor-bearing animals with CA-4948 results in the downregulation of ERK and MAPK signaling in addition to decreased NF-κB. These intracellular changes are associated with a survival advantage. Conclusions: IRAK-4 is an attractive target in PCNSL and MBM. The inhibition of IRAK-4 with CA-4948 downregulates the expression of important transcription factors involved in tumor growth and proliferation. CA-4948 is currently being investigated in clinical trials for relapsed and refractory lymphoma and warrants further translation into PCNSL and MBM.

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Section: Introductionmentioning

confidence: 99%

Oral IRAK-4 Inhibitor CA-4948 Is Blood-Brain Barrier Penetrant and Has Single-Agent Activity against CNS Lymphoma and Melanoma Brain Metastases

Roemeling

Doonan

Klippel

et al. 2023

Clinical Cancer Research

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“…The supporting information can be downloaded at: . References [ 4 , 14 , 62 , 63 ] are cited in the supplementary materials.…”

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confidence: 99%

Modulation of Inflammatory Cytokine Production in Human Monocytes by cGMP and IRAK3

Nguyen

Axell

Turek

et al. 2022

IJMS

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Interleukin-1 receptor-associated kinase-3 (IRAK3) is a critical checkpoint molecule of inflammatory responses in the innate immune system. The pseudokinase domain of IRAK3 contains a guanylate cyclase (GC) centre that generates small amounts of cyclic guanosine monophosphate (cGMP) associated with IRAK3 functions in inflammation. However, the mechanisms of IRAK3 actions are poorly understood. The effects of low cGMP levels on inflammation are unknown, therefore a dose–response effect of cGMP on inflammatory markers was assessed in THP-1 monocytes challenged with lipopolysaccharide (LPS). Sub-nanomolar concentrations of membrane permeable 8-Br-cGMP reduced LPS-induced NFκB activity, IL-6 and TNF-α cytokine levels. Pharmacologically upregulating cellular cGMP levels using a nitric oxide donor reduced cytokine secretion. Downregulating cellular cGMP using a soluble GC inhibitor increased cytokine levels. Knocking down IRAK3 in THP-1 cells revealed that unlike the wild type cells, 8-Br-cGMP did not suppress inflammatory responses. Complementation of IRAK3 knockdown cells with wild type IRAK3 suppressed cytokine production while complementation with an IRAK3 mutant at GC centre only partially restored this function. Together these findings indicate low levels of cGMP form a critical component in suppressing cytokine production and in mediating IRAK3 action, and this may be via a cGMP enriched nanodomain formed by IRAK3 itself.

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TRAF inhibition drives cancer cell apoptosis and improves retinoic acid sensitivity in multiple cancers models

et al. 2023

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TNF receptor-associated factors (TRAFs) are signaling adaptor proteins that play a crucial role in regulating cellular receptors’ signaling transduction to downstream pathways and exert multifaceted roles in regulating signaling pathways, cell survival, and carcinogenesis. The 13-cis-retinoic acid (RA), an active metabolite of vitamin A, exhibits anti-cancer properties, but the development of retinoic acid resistance poses a challenge in clinical application. This study aimed to investigate the relationship between TRAFs and retinoic acid sensitivity in various cancers. Here, we revealed that TRAFs’ expression varied significantly across The Cancer Genome Atlas (TCGA) cancer cohorts and human cancer cell lines. Additionally, inhibiting TRAF4, TRAF5, or TRAF6 improved retinoic acid sensitivity and reduced colony formation in ovarian cancer and melanoma cells. Mechanistically, knocking down TRAF4, TRAF5, or TRAF6 in retinoic acid-treated cancer cell lines increased the levels of procaspase 9 and induced cell apoptosis. Further in vivo studies using the SK-OV-3 and MeWo xenograft models confirmed the anti-tumor effects of TRAF knockdown combined with retinoic acid treatment. These findings support that combination therapy with retinoic acid and TRAF silencing may offer significant therapeutic advantages in treating melanoma and ovarian cancers.

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Induction of IRAK-M in melanoma induces caspase-3 dependent apoptosis by reducing TRAF6 and calpastatin levels

Cited by 4 publications

References 24 publications

Oral IRAK-4 Inhibitor CA-4948 Is Blood-Brain Barrier Penetrant and Has Single-Agent Activity against CNS Lymphoma and Melanoma Brain Metastases

Oral IRAK-4 Inhibitor CA-4948 Is Blood-Brain Barrier Penetrant and Has Single-Agent Activity against CNS Lymphoma and Melanoma Brain Metastases

Modulation of Inflammatory Cytokine Production in Human Monocytes by cGMP and IRAK3

TRAF inhibition drives cancer cell apoptosis and improves retinoic acid sensitivity in multiple cancers models

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