17-Aminogeldanamycin selectively diminishes IRE1α-XBP1s pathway activity and cooperatively induces apoptosis with MEK1/2 and BRAFV600E inhibitors in melanoma cells of different genetic subtypes

Autor: Mielczarek-Lewandowska, Aleksandra, Sztiller-Sikorska, Malgorzata, Osrodek, Marta, Czyz, Malgorzata, Hartman, Mariusz L.
Rok vydání: 2019
Předmět:
X-Box Binding Protein 1
0301 basic medicine
Cancer Research
MAP Kinase Kinase 2
Clinical Biochemistry
MAP Kinase Kinase 1
Pharmaceutical Science
Apoptosis
GTP Phosphohydrolases
Targeted therapy
chemistry.chemical_compound
0302 clinical medicine
Benzoquinones
Vemurafenib
Melanoma
Endoplasmic Reticulum Chaperone BiP
Heat-Shock Proteins
Trametinib
biology
Chemistry
Geldanamycin
Endoplasmic Reticulum Stress
Hsp90
030220 oncology & carcinogenesis
Signal Transduction
medicine.drug
Proto-Oncogene Proteins B-raf
Cell Survival
Lactams
Macrocyclic
Antineoplastic Agents
Protein Serine-Threonine Kinases
Article
03 medical and health sciences
Cell Line
Tumor
IRE-1α
Endoribonucleases
medicine
Humans
Protein Kinase Inhibitors
HSP90 inhibitors
Pharmacology
ATF6
Biochemistry (medical)
Membrane Proteins
Cell Biology
17-aminogeldanamycin
medicine.disease
030104 developmental biology
Unfolded Protein Response
biology.protein
Unfolded protein response
Cancer research
Zdroj: Apoptosis
ISSN: 1573-675X
1360-8185
DOI: 10.1007/s10495-019-01542-y
Popis: Outcomes of melanoma patient treatment remain unsatisfactory despite accessibility of oncoprotein-targeting drugs and immunotherapy. Here, we reported that 17-aminogeldanamycin more potently activated caspase-3/7 in BRAFV600E melanoma cells than geldanamycin, another inhibitor of heat shock protein 90 (HSP90). 17-aminogeldanamycin alleviated self-triggered compensatory increase in HSP70 mRNA level and induced endoplasmic reticulum (ER) stress, which was followed by selective diminution of cytoprotective IRE1α-XBP1s pathway activity of unfolded protein response (UPR), inhibition of ERK1/2 activity and induction of apoptosis. Concomitantly, ATF6/p50 level and expression of PERK-dependent genes, CHOP and BIM, remained unaltered. This might result from an inframe deletion in EIF2AK3 leading to a PERKL21del variant revealed by whole-exome sequencing in melanoma cell lines. 17-aminogeldanamycin exhibited similar activity in NRASQ61R melanoma cells that harbored a heterozygous inactivating variant of NAD(P)H:quinone oxidoreductase 1 (NQO1P187S). In addition, 17-aminogeldanamycin acted cooperatively with trametinib (an inhibitor of MEK1/2) and vemurafenib (an inhibitor of BRAFV600E) in induction of apoptosis in melanoma cell lines as evidenced by in-cell caspase-3/7 activation and PARP cleavage that occurred earlier compared with either drug used alone. As trametinib and vemurafenib did not significantly affect HSP70 and GRP78 transcript levels, cooperation of MEK/BRAFV600E inhibitors and 17-aminogeldanamycin might result from a concurrent inhibition of the RAS/RAF/MEK/ERK cascade and IRE1α-dependent signaling, and cell-intrinsic ER homeostasis can determine the extent of the drug cooperation. Our study indicates that 17-aminogeldanamycin takes several advantages compared with other HSP90-targeting compounds, and can complement activity of BRAF/MEK inhibitors in melanoma cells of different genetic subtypes. Electronic supplementary material The online version of this article (10.1007/s10495-019-01542-y) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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