Abstract
The BRAF V600E mutation leads to constitutive activation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway and its downstream effector responses. Uncovering the hidden downstream effectors can aid in understanding melanoma biology and improve targeted therapy efficacy. The inflammasome sensor, NACHT, LRR, and PYD domains-containing protein 1 (NLRP1), is responsible for IL-1β maturation and itself is a melanoma tumor promoter. Here, we report that NLRP1 is a downstream effector of MAPK/ERK signaling through the activating transcription factor 4 (ATF4), creating regulation in metastatic melanoma cells. We confirmed that the NLRP1 gene is a target of ATF4. Interestingly, ATF4/NLRP1 regulation by the MAPK/ERK pathway uses distinct mechanisms in melanoma cells before and after the acquired resistance to targeted therapy. In parental cells, ATF4/NLRP1 is regulated by the MAPK/ERK pathway through the ribosomal S6 kinase 2 (RSK2). However, vemurafenib (VEM) and trametinib (TRA)-resistant cells lose the signaling via RSK2 and activate the cAMP/protein kinase A (PKA) pathway to redirect ATF4/NLRP1. Therefore, NLRP1 expression and IL-1β secretion were downregulated in response to VEM and TRA in parental cells but enhanced in drug-resistant cells. Lastly, silencing NLRP1 in drug-resistant cells reduced their cell growth and inhibited colony formation. In summary, we demonstrated that NLRP1 functions downstream of the MAPK/ERK signaling via ATF4 and is a player of targeted therapy resistance in melanoma. Targeting NLRP1 may improve the therapeutic efficacy of targeted therapy in melanoma.
Highlights
Melanoma is a highly aggressive cancer causing the majority of skin cancer deaths.Approximately 50% of melanoma patients harbor a BRAF, V600E [1], mutation in tumors, which leads to increased expression of downstream effectors, favoring tumor survival [2]
We first determined the mechanism of NLRP1 regulation by the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway using drug-sensitive melanoma cells
We provide further evidence that NLRP1 lies downstream of the endoplasmic reticulum (ER) stress signaling cascade, possibly through the protein kinase R-like ER kinase (PERK)/activating transcription factor 4 (ATF4) in melanoma cells
Summary
Melanoma is a highly aggressive cancer causing the majority of skin cancer deaths. Approximately 50% of melanoma patients harbor a BRAF, V600E [1], mutation in tumors, which leads to increased expression of downstream effectors, favoring tumor survival [2]. It has been suggested that the inflammatory tumor microenvironment, driven by tumor-intrinsic signaling pathways, is a major checkpoint to therapeutic efficacy [4]. Tumorpromoting stromal cells, such as tumor-associated macrophages, dendritic cells, and fibroblasts, sustain tumor cell survival, immunosuppression, and drug resistance by producing diverse inflammatory mediators. NLRP1 gain-offunction mutations have been demonstrated to contribute to constitutive inflammasome activation and IL-1β signaling in skin inflammation and cancer development [11]. We further demonstrate, for the first time, that NLRP1 functions downstream of the MAPK/ERK signaling and contributes to acquired targeted therapy resistance in melanoma. Our findings may help develop resistance mechanism-targeted inhibitors as a strategy to improve the efficacy of current therapeutics
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