Cargando…
NLRP1 Functions Downstream of the MAPK/ERK Signaling via ATF4 and Contributes to Acquired Targeted Therapy Resistance in Human Metastatic Melanoma
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...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823742/ https://www.ncbi.nlm.nih.gov/pubmed/33396632 http://dx.doi.org/10.3390/ph14010023 |
_version_ | 1783639908396564480 |
---|---|
author | Zhai, Zili Vaddi, Prasanna K. Samson, Jenny Mae Takegami, Tomoya Fujita, Mayumi |
author_facet | Zhai, Zili Vaddi, Prasanna K. Samson, Jenny Mae Takegami, Tomoya Fujita, Mayumi |
author_sort | Zhai, Zili |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-7823742 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-78237422021-01-24 NLRP1 Functions Downstream of the MAPK/ERK Signaling via ATF4 and Contributes to Acquired Targeted Therapy Resistance in Human Metastatic Melanoma Zhai, Zili Vaddi, Prasanna K. Samson, Jenny Mae Takegami, Tomoya Fujita, Mayumi Pharmaceuticals (Basel) Article 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. MDPI 2020-12-30 /pmc/articles/PMC7823742/ /pubmed/33396632 http://dx.doi.org/10.3390/ph14010023 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Zhai, Zili Vaddi, Prasanna K. Samson, Jenny Mae Takegami, Tomoya Fujita, Mayumi NLRP1 Functions Downstream of the MAPK/ERK Signaling via ATF4 and Contributes to Acquired Targeted Therapy Resistance in Human Metastatic Melanoma |
title | NLRP1 Functions Downstream of the MAPK/ERK Signaling via ATF4 and Contributes to Acquired Targeted Therapy Resistance in Human Metastatic Melanoma |
title_full | NLRP1 Functions Downstream of the MAPK/ERK Signaling via ATF4 and Contributes to Acquired Targeted Therapy Resistance in Human Metastatic Melanoma |
title_fullStr | NLRP1 Functions Downstream of the MAPK/ERK Signaling via ATF4 and Contributes to Acquired Targeted Therapy Resistance in Human Metastatic Melanoma |
title_full_unstemmed | NLRP1 Functions Downstream of the MAPK/ERK Signaling via ATF4 and Contributes to Acquired Targeted Therapy Resistance in Human Metastatic Melanoma |
title_short | NLRP1 Functions Downstream of the MAPK/ERK Signaling via ATF4 and Contributes to Acquired Targeted Therapy Resistance in Human Metastatic Melanoma |
title_sort | nlrp1 functions downstream of the mapk/erk signaling via atf4 and contributes to acquired targeted therapy resistance in human metastatic melanoma |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823742/ https://www.ncbi.nlm.nih.gov/pubmed/33396632 http://dx.doi.org/10.3390/ph14010023 |
work_keys_str_mv | AT zhaizili nlrp1functionsdownstreamofthemapkerksignalingviaatf4andcontributestoacquiredtargetedtherapyresistanceinhumanmetastaticmelanoma AT vaddiprasannak nlrp1functionsdownstreamofthemapkerksignalingviaatf4andcontributestoacquiredtargetedtherapyresistanceinhumanmetastaticmelanoma AT samsonjennymae nlrp1functionsdownstreamofthemapkerksignalingviaatf4andcontributestoacquiredtargetedtherapyresistanceinhumanmetastaticmelanoma AT takegamitomoya nlrp1functionsdownstreamofthemapkerksignalingviaatf4andcontributestoacquiredtargetedtherapyresistanceinhumanmetastaticmelanoma AT fujitamayumi nlrp1functionsdownstreamofthemapkerksignalingviaatf4andcontributestoacquiredtargetedtherapyresistanceinhumanmetastaticmelanoma |