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Investigating mechanisms for acquired resistance to HDAC inhibitors in histiocytic lymphoma U‐937 cells
Author(s) -
Burnett Matthew,
Carle Sigrid
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.00619
Subject(s) - autophagy , protein kinase b , glycolysis , acetylation , signal transduction , kinase , microbiology and biotechnology , downregulation and upregulation , cancer research , biology , chemistry , biochemistry , apoptosis , enzyme , gene
Xyzidepsin (Xyzi) is an analog of the FDA approved HDAC inhibitor FK228. HDAC inhibitors increase acetylation of histones and other proteins modified by Histone Acetyltransferases (HATs). Through MTT assay analysis we determined the IC 50 for Xyzi to be 0.567 μM. Several resistance mechanisms have been suggested for HDAC inhibitors, including the protein ABCB1/MDR1/P‐glycoprotein upregulation, and changes to signal transduction pathways and glycolysis. To further understand mechanisms of resistance a dose escalation protocol with increasing concentration of HDAC inhibitor is used. Autophagy is identified as a resistance mechanism for vorinastat in U‐937 cells. Interestingly, Akt (Protein kinase B, PKB), is an upstream kinase regulatory protein related to glucose metabolism, MDR‐1 expression, autophagy, cell proliferation and apoptosis. Previous studies suggest an association between the regulation of autophagy by Akt through glycolytic pathways, which may indicate a key role of regulator isoenzymes for the glycolysis enzyme 6‐Phosphofructo‐2‐kinase/fructose2,6‐biphosphatase such as, PFKFB3 and PFKB 4 , in the development of drug resistance. We intend to uncover possible shifts in gene expression which could indicate a combined effect of previously observed resistance mechanisms or alternative mechanism to accommodate an increasing HDAC concentration. The mechanisms for Xyzi and other HDAC inhibitors like as SAHA could then be compared.