Tags

Type your tag names separated by a space and hit enter

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.
Apoptosis. 2019 08; 24(7-8):596-611.A

Abstract

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.

Authors+Show Affiliations

Department of Molecular Biology of Cancer, Medical University of Lodz, 6/8 Mazowiecka Street, 92-215, Lodz, Poland.Department of Molecular Biology of Cancer, Medical University of Lodz, 6/8 Mazowiecka Street, 92-215, Lodz, Poland.Department of Molecular Biology of Cancer, Medical University of Lodz, 6/8 Mazowiecka Street, 92-215, Lodz, Poland.Department of Molecular Biology of Cancer, Medical University of Lodz, 6/8 Mazowiecka Street, 92-215, Lodz, Poland.Department of Molecular Biology of Cancer, Medical University of Lodz, 6/8 Mazowiecka Street, 92-215, Lodz, Poland. mariusz.hartman@umed.lodz.pl.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30989459

Citation

Mielczarek-Lewandowska, Aleksandra, et al. "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." Apoptosis : an International Journal On Programmed Cell Death, vol. 24, no. 7-8, 2019, pp. 596-611.
Mielczarek-Lewandowska A, Sztiller-Sikorska M, Osrodek M, et al. 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. Apoptosis. 2019;24(7-8):596-611.
Mielczarek-Lewandowska, A., Sztiller-Sikorska, M., Osrodek, M., Czyz, M., & Hartman, M. L. (2019). 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. Apoptosis : an International Journal On Programmed Cell Death, 24(7-8), 596-611. https://doi.org/10.1007/s10495-019-01542-y
Mielczarek-Lewandowska A, et al. 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. Apoptosis. 2019;24(7-8):596-611. PubMed PMID: 30989459.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Mielczarek-Lewandowska,Aleksandra, AU - Sztiller-Sikorska,Malgorzata, AU - Osrodek,Marta, AU - Czyz,Malgorzata, AU - Hartman,Mariusz L, PY - 2019/4/17/pubmed PY - 2019/4/17/medline PY - 2019/4/17/entrez KW - 17-aminogeldanamycin KW - Endoplasmic reticulum stress KW - HSP90 inhibitors KW - IRE-1α KW - Melanoma KW - Targeted therapy SP - 596 EP - 611 JF - Apoptosis : an international journal on programmed cell death JO - Apoptosis VL - 24 IS - 7-8 N2 - 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. SN - 1573-675X UR - https://www.unboundmedicine.com/medline/citation/30989459/17_Aminogeldanamycin_selectively_diminishes_IRE1α_XBP1s_pathway_activity_and_cooperatively_induces_apoptosis_with_MEK1/2_and_BRAFV600E_inhibitors_in_melanoma_cells_of_different_genetic_subtypes_ L2 - https://doi.org/10.1007/s10495-019-01542-y DB - PRIME DP - Unbound Medicine ER -