Nitric oxide antagonism to glioblastoma photodynamic therapy and mitigation thereof by BET bromodomain inhibitor JQ1. J Biol Chem 2018 Apr 06;293(14):5345-5359
Date
02/15/2018Pubmed ID
29440272Pubmed Central ID
PMC5892570DOI
10.1074/jbc.RA117.000443Scopus ID
2-s2.0-85045064956 (requires institutional sign-in at Scopus site) 53 CitationsAbstract
Endogenous nitric oxide (NO) generated by inducible NO synthase (iNOS) promotes glioblastoma cell proliferation and invasion and also plays a key role in glioblastoma resistance to chemotherapy and radiotherapy. Non-ionizing photodynamic therapy (PDT) has anti-tumor advantages over conventional glioblastoma therapies. Our previous studies revealed that glioblastoma U87 cells up-regulate iNOS after a photodynamic challenge and that the resulting NO not only increases resistance to apoptosis but renders surviving cells more proliferative and invasive. These findings were largely based on the effects of inhibiting iNOS activity and scavenging NO. Demonstrating now that iNOS expression in photostressed U87 cells is mediated by NF-κB, we hypothesized that (i) recognition of acetylated lysine (acK) on NF-κB p65/RelA by bromodomain and extra-terminal (BET) protein Brd4 is crucial; and (ii) by suppressing iNOS expression, a BET inhibitor (JQ1) would attenuate the negative effects of photostress. The following evidence was obtained. (i) Like iNOS, Brd4 protein and p65-acK levels increased severalfold in photostressed cells. (ii) JQ1 at minimally toxic concentrations had no effect on Brd4 or p65-acK up-regulation after PDT but strongly suppressed iNOS, survivin, and Bcl-xL up-regulation, along with the growth and invasion spurt of PDT-surviving cells. (iii) JQ1 inhibition of NO production in photostressed cells closely paralleled that of growth/invasion inhibition. (iv) Finally, at 1% the concentration of iNOS inhibitor 1400W, JQ1 reduced post-PDT cell aggressiveness to a far greater extent. This is the first evidence for BET inhibitor targeting of iNOS expression in cancer cells and how such targeting can markedly improve therapeutic efficacy.
Author List
Fahey JM, Stancill JS, Smith BC, Girotti AWAuthors
Albert W. Girotti PhD Adjunct Professor in the Biochemistry department at Medical College of WisconsinBrian C. Smith PhD Associate Professor in the Biochemistry department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
ApoptosisAzepines
Cell Cycle Proteins
Cell Line, Tumor
Cell Proliferation
Cell Survival
Glioblastoma
Humans
NF-kappa B
Nitric Oxide
Nitric Oxide Synthase
Nitric Oxide Synthase Type II
Nuclear Proteins
Photochemotherapy
Proteins
Protoporphyrins
Transcription Factors
Triazoles
Up-Regulation
