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Open AccessArticle

Proteomic Analysis of Breast Cancer Resistance to the Anticancer Drug RH1 Reveals the Importance of Cancer Stem Cells

1
Proteomics Center, Institute of Biochemistry, Vilnius University Life Sciences Center, Vilnius University, 10223 Vilnius, Lithuania
2
Laboratory of Molecular Oncology, National Cancer Institute, 08660 Vilnius, Lithuania
3
MAP Kinase Resource, 3027 Bern, Switzerland
4
Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
*
Author to whom correspondence should be addressed.
These authors contributed equally to the work.
Cancers 2019, 11(7), 972; https://doi.org/10.3390/cancers11070972
Received: 27 June 2019 / Accepted: 8 July 2019 / Published: 11 July 2019
(This article belongs to the Collection Kinases and Cancer)
Antitumor drug resistance remains a major challenge in cancer chemotherapy. Here we investigated the mechanism of acquired resistance to a novel anticancer agent RH1 designed to be activated in cancer cells by the NQO1 enzyme. Data show that in some cancer cells RH1 may act in an NQO1-independent way. Differential proteomic analysis of breast cancer cells with acquired resistance to RH1 revealed changes in cell energy, amino acid metabolism and G2/M cell cycle transition regulation. Analysis of phosphoproteomics and protein kinase activity by multiplexed kinase inhibitor beads showed an increase in the activity of protein kinases involved in the cell cycle and stemness regulation and downregulation of proapoptotic kinases such as JNK in RH1-resistant cells. Suppression of JNK leads to the increase of cancer cell resistance to RH1. Moreover, resistant cells have enhanced expression of stem cell factor (SCF) and stem cell markers. Inhibition of SCF receptor c-KIT resulted in the attenuation of cancer stem cell enrichment and decreased amounts of tumor-initiating cells. RH1-resistant cells also acquire resistance to conventional therapeutics while remaining susceptible to c-KIT-targeted therapy. Data show that RH1 can be useful to treat cancers in the NQO1-independent way, and targeting of the cancer stem cells might be an effective approach for combating resistance to RH1 therapy. View Full-Text
Keywords: RH1; chemotherapy; cancer drug resistance; JNK; c-KIT; protein kinases; label-free proteomics; MIBs; phosphoproteome; cancer stem cells RH1; chemotherapy; cancer drug resistance; JNK; c-KIT; protein kinases; label-free proteomics; MIBs; phosphoproteome; cancer stem cells
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Kuciauskas, D.; Dreize, N.; Ger, M.; Kaupinis, A.; Zemaitis, K.; Stankevicius, V.; Suziedelis, K.; Cicenas, J.; Graves, L.M.; Valius, M. Proteomic Analysis of Breast Cancer Resistance to the Anticancer Drug RH1 Reveals the Importance of Cancer Stem Cells. Cancers 2019, 11, 972.

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