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

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

Publication date: Apr 15, 2019

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 BRAF 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 PERK variant revealed by whole-exome sequencing in melanoma cell lines. 17-aminogeldanamycin exhibited similar activity in NRAS melanoma cells that harbored a heterozygous inactivating variant of NAD(P)H:quinone oxidoreductase 1 (NQO1). In addition, 17-aminogeldanamycin acted cooperatively with trametinib (an inhibitor of MEK1/2) and vemurafenib (an inhibitor of BRAF) 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/BRAF 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.

Concepts Keywords
Accessibility Apoptosis
Apoptosis Hsp90
BIM Trametinib
BRAF Vemurafenib
Caspase 3 MEK inhibitor
CHOP Chloroarenes
Cleavage Melanoma
Complement Molecular chaperones
Concurrent Cancer treatments
Endoplasmic Reticulum Chemical compounds
ER Stress Heat shock proteins
ERK Medicine
ERK1 Branches of biology
Exome Immunotherapy
Genetic
Heat Shock
Heterozygous
Homeostasis
HSP70
HSP90
Immunotherapy
Inhibitor
MEK
Melanoma
MRNA
NADPH
Oncoprotein
Oxidoreductase
PARP
Quinone
RAF
RAS
Sequencing
Vemurafenib

Semantics

Type Source Name
disease MESH Endoplasmic reticulum stress
gene UNIPROT ZHX2
drug DRUGBANK Rasagiline
gene UNIPROT MAP2K7
gene UNIPROT HSPA5
gene UNIPROT PARP1
gene UNIPROT COL11A2
drug DRUGBANK Vemurafenib
drug DRUGBANK Trametinib
gene UNIPROT NQO1
gene UNIPROT NRAS
gene UNIPROT BCL2L11
gene UNIPROT DDIT3
gene UNIPROT EIF2AK3
gene UNIPROT CD40
gene UNIPROT NFKB1
gene UNIPROT ARHGEF7
gene UNIPROT ASCC1
gene UNIPROT ATF6
gene UNIPROT MAPK3
gene UNIPROT HSPA4
gene UNIPROT HSP90AA1
disease MESH shock
drug DRUGBANK Geldanamycin
pathway BSID Melanoma
disease DOID melanoma
disease MESH melanoma
gene UNIPROT BRAF
gene UNIPROT MAP2K1
pathway BSID Apoptosis
gene UNIPROT ERN1

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