Dual Targeting of BRAF and mTOR Signaling in Melanoma Cells
with Pyridinyl Imidazole Compounds

J 2020

Dual Targeting of BRAF and mTOR Signaling in Melanoma Cells with Pyridinyl Imidazole Compounds

PALUŠOVÁ, Veronika; Tereza RENZOVÁ; Amandine VERLANDE; Tereza VACLOVÁ; Michaela MEDKOVÁ et. al.

Základní údaje

Originální název

Dual Targeting of BRAF and mTOR Signaling in Melanoma Cells with Pyridinyl Imidazole Compounds

Autoři

Vydání

Cancers, BASEL, MDPI, 2020, 2072-6694

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

30204 Oncology

Stát vydavatele

Švýcarsko

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 6.639

Kód RIV

RIV/00216224:14110/20:00116135

Organizační jednotka

Lékařská fakulta

DOI

https://doi.org/10.3390/cancers12061516

UT WoS

000549386200001

EID Scopus

2-s2.0-85086338194

Klíčová slova anglicky

melanoma; BRAF V600E; BRAF inhibitor; small molecule drug; pyridinyl imidazole; endosome; lysosome; mTORC1; ER stress

Štítky

14110513, 14110517, 143160, CF NMR, podil, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 5. 3. 2025 13:17, Mgr. Eva Dubská

Anotace

V originále

BRAF inhibitors can delay the progression of metastatic melanoma, but resistance usually emerges, leading to relapse. Drugs simultaneously targeting two or more pathways essential for cancer growth could slow or prevent the development of resistant clones. Here, we identified pyridinyl imidazole compounds SB202190, SB203580, and SB590885 as dual inhibitors of critical proliferative pathways in human melanoma cells bearing the V600E activating mutation of BRAF kinase. We found that the drugs simultaneously disrupt the BRAF V600E-driven extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) activity and the mechanistic target of rapamycin complex 1 (mTORC1) signaling in melanoma cells. Pyridinyl imidazole compounds directly inhibit BRAF V600E kinase. Moreover, they interfere with the endolysosomal compartment, promoting the accumulation of large acidic vacuole-like vesicles and dynamic changes in mTOR signaling. A transient increase in mTORC1 activity is followed by the enrichment of the Ragulator complex protein p18/LAMTOR1 at contact sites of large vesicles and delocalization of mTOR from the lysosomes. The induced disruption of the endolysosomal pathway not only disrupts mTORC1 signaling, but also renders melanoma cells sensitive to endoplasmic reticulum (ER) stress. Our findings identify new activities of pharmacologically relevant small molecule compounds and provide a biological rationale for the development of anti-melanoma therapeutics based on the pyridinyl imidazole core.

Návaznosti

MUNI/A/0951/2019, interní kód MU

Název: Buněčná a molekulární biologie pro Biomedicínské vědy

Investor: Masarykova univerzita, Buněčná a molekulární biologie pro Biomedicínské vědy, DO R. 2020_Kategorie A - Specifický výzkum - Studentské výzkumné projekty

MUNI/A/1087/2018, interní kód MU

Název: Molekulární a buněčná biologie pro biomedicínské vědy

Investor: Masarykova univerzita, Molekulární a buněčná biologie pro biomedicínské vědy, DO R. 2020_Kategorie A - Specifický výzkum - Studentské výzkumné projekty

NV19-08-00450, projekt VaV

Název: Atomárně rozlišená NMR spektroskopie in vivo jako nástroj pro biologické testování terapeuticky významných cílů v genomové ne-kanonické DNA a jejich interakcí s léčivy ve fenotypově diverzifikovaných nádorových buňkách.

Investor: Ministerstvo zdravotnictví ČR, Atomically resolved in vivo NMR spectroscopy as a novel tool for biological testing of therapeutically important genomic non-canonical DNA targets and their interactions with drugs in phenotypically diversified cancer cells.

90127, velká výzkumná infrastruktura

Název: CIISB II

90129, velká výzkumná infrastruktura

Název: Czech-BioImaging II

Citovat

PALUŠOVÁ, Veronika; Tereza RENZOVÁ; Amandine VERLANDE; Tereza VACLOVÁ; Michaela MEDKOVÁ; Linda CETLOVÁ; Miroslava SEDLÁČKOVÁ; Hana HŘÍBKOVÁ; Iva SLANINOVÁ; Miriama KRUTÁ; Vladimír ROTREKL; Hana UHLIROVA; Aneta KRIZOVA; Radim CHMELIK; Pavel VESELY; Michaela KRAFČÍKOVÁ; Lukáš TRANTÍREK; Kay Oliver SCHINK a Stjepan ULDRIJAN. Dual Targeting of BRAF and mTOR Signaling in Melanoma Cells with Pyridinyl Imidazole Compounds. Cancers. BASEL: MDPI, 2020, roč. 12, č. 6, s. 1-24. ISSN 2072-6694. Dostupné z: https://doi.org/10.3390/cancers12061516.

@article{1673179,
   author = {Palušová, Veronika and Renzová, Tereza and Verlande, Amandine and Vaclová, Tereza and Medková, Michaela and Cetlová, Linda and Sedláčková, Miroslava and Hříbková, Hana and Slaninová, Iva and Krutá, Miriama and Rotrekl, Vladimír and Uhlirova, Hana and Krizova, Aneta and Chmelik, Radim and Vesely, Pavel and Krafčíková, Michaela and Trantírek, Lukáš and Schink, Kay Oliver and Uldrijan, Stjepan},
   article_location = {BASEL},
   article_number = {6},
   doi = {https://doi.org/10.3390/cancers12061516},
   keywords = {melanoma; BRAF V600E; BRAF inhibitor; small molecule drug; pyridinyl imidazole; endosome; lysosome; mTORC1; ER stress},
   language = {eng},
   issn = {2072-6694},
   journal = {Cancers},
   title = {Dual Targeting of BRAF and mTOR Signaling in Melanoma Cells with Pyridinyl Imidazole Compounds},
   url = {https://www.mdpi.com/2072-6694/12/6/1516},
   volume = {12},
   year = {2020}
}

TY  - JOUR
ID  - 1673179
AU  - Palušová, Veronika - Renzová, Tereza - Verlande, Amandine - Vaclová, Tereza - Medková, Michaela - Cetlová, Linda - Sedláčková, Miroslava - Hříbková, Hana - Slaninová, Iva - Krutá, Miriama - Rotrekl, Vladimír - Uhlirova, Hana - Krizova, Aneta - Chmelik, Radim - Vesely, Pavel - Krafčíková, Michaela - Trantírek, Lukáš - Schink, Kay Oliver - Uldrijan, Stjepan
PY  - 2020
TI  - Dual Targeting of BRAF and mTOR Signaling in Melanoma Cells with Pyridinyl Imidazole Compounds
JF  - Cancers
VL  - 12
IS  - 6
SP  - 1-24
EP  - 1-24
PB  - MDPI
SN  - 20726694
KW  - melanoma
KW  - BRAF V600E
KW  - BRAF inhibitor
KW  - small molecule drug
KW  - pyridinyl imidazole
KW  - endosome
KW  - lysosome
KW  - mTORC1
KW  - ER stress
UR  - https://www.mdpi.com/2072-6694/12/6/1516
L2  - https://www.mdpi.com/2072-6694/12/6/1516
N2  - BRAF inhibitors can delay the progression of metastatic melanoma, but resistance usually emerges, leading to relapse. Drugs simultaneously targeting two or more pathways essential for cancer growth could slow or prevent the development of resistant clones. Here, we identified pyridinyl imidazole compounds SB202190, SB203580, and SB590885 as dual inhibitors of critical proliferative pathways in human melanoma cells bearing the V600E activating mutation of BRAF kinase. We found that the drugs simultaneously disrupt the BRAF V600E-driven extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) activity and the mechanistic target of rapamycin complex 1 (mTORC1) signaling in melanoma cells. Pyridinyl imidazole compounds directly inhibit BRAF V600E kinase. Moreover, they interfere with the endolysosomal compartment, promoting the accumulation of large acidic vacuole-like vesicles and dynamic changes in mTOR signaling. A transient increase in mTORC1 activity is followed by the enrichment of the Ragulator complex protein p18/LAMTOR1 at contact sites of large vesicles and delocalization of mTOR from the lysosomes. The induced disruption of the endolysosomal pathway not only disrupts mTORC1 signaling, but also renders melanoma cells sensitive to endoplasmic reticulum (ER) stress. Our findings identify new activities of pharmacologically relevant small molecule compounds and provide a biological rationale for the development of anti-melanoma therapeutics based on the pyridinyl imidazole core.
ER  -

PALUŠOVÁ, Veronika; Tereza RENZOVÁ; Amandine VERLANDE; Tereza VACLOVÁ; Michaela MEDKOVÁ; Linda CETLOVÁ; Miroslava SEDLÁČKOVÁ; Hana HŘÍBKOVÁ; Iva SLANINOVÁ; Miriama KRUTÁ; Vladimír ROTREKL; Hana UHLIROVA; Aneta KRIZOVA; Radim CHMELIK; Pavel VESELY; Michaela KRAFČÍKOVÁ; Lukáš TRANTÍREK; Kay Oliver SCHINK a Stjepan ULDRIJAN. Dual Targeting of BRAF and mTOR Signaling in Melanoma Cells with Pyridinyl Imidazole Compounds. \textit{Cancers}. BASEL: MDPI, 2020, roč.~12, č.~6, s.~1-24. ISSN~2072-6694. Dostupné z: https://doi.org/10.3390/cancers12061516.

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