OSU-03012 suppresses GRP78/BiP expression that causes PERK-dependent increases in tumor cell killing.

Cancer Biology & Therapy
Laurence BoothPaul Dent

Abstract

We have further defined mechanism(s) by which the drug OSU-03012 (OSU) kills tumor cells. OSU lethality was suppressed by knock down of PERK and enhanced by knock down of ATF6 and IRE1α. OSU treatment suppressed expression of the chaperone, BiP/GRP78, and did so through reduced stability of the protein. Knock down of BiP/GRP78 further enhanced OSU lethality. Overexpression of BiP/GRP78 abolished OSU toxicity. Pre-treatment of cells with OSU enhanced radiosensitivity to a greater extent than concomitant or sequential drug treatment with radiation exposure. Expression of a mutant active p110 PI3K, or mutant active forms of the EGFR in GBM cells did not differentially suppress OSU killing. In contrast loss of PTEN function reduced OSU lethality, without altering AKT, p70 S6K or mTOR activity, or the drug's ability to radiosensitize GBM cells. Knock down of PTEN protected cells from OSU and radiation treatment whereas re-expression of PTEN facilitated drug lethality and radiosensitization. In a dose-dependent fashion OSU prolonged the survival of mice carrying GBM tumors and interacted with radiotherapy to further prolong survival. Collectively, our data show that reduced BiP/GRP78 levels play a key role in OSU-3012 toxicity in GBM...Continue Reading

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Citations

Oct 7, 2014·Cardiovascular Drugs and Therapy·Ling LiXiaowei Yan
Nov 17, 2014·Cytotechnology·Nizar M MhaidatSulaiman Swaidan
Oct 11, 2014·Journal of Cellular Physiology·Laurence BoothPaul Dent
Sep 25, 2012·Biochemical Pharmacology·Axel H Schönthal
Oct 13, 2015·Molecular and Cellular Endocrinology·Robert ClarkeJ Michael Dixon
Dec 9, 2014·Cancer Biology & Therapy·Laurence BoothPaul Dent
Sep 20, 2012·Cancer Biology & Therapy·Laurence BoothPaul Dent
Feb 18, 2015·DNA and Cell Biology·Laurence BoothPaul Dent
Dec 30, 2014·Journal of Cellular Physiology·Laurence BoothPaul Dent
May 22, 2019·Current Topics in Medicinal Chemistry·Guangyu ZhangZhao V Wang
Aug 9, 2019·Current Topics in Medicinal Chemistry·Bingqian YanWei Fu
Aug 12, 2014·Molecular Cancer Therapeutics·Laurence BoothPaul Dent
Feb 14, 2021·Journal of Cellular Physiology·Zahra Hasanpour SegherlouMohammad Zarei
Dec 29, 2020·Frontiers in Oncology·Kristie LiuFrank J Attenello
Mar 5, 2019·Biochemical Pharmacology·Christian Bailly, Michael J Waring
Aug 17, 2021·Anti-cancer Drugs·Paul DentJohn F Hancock
Oct 14, 2021·Microbiology and Molecular Biology Reviews : MMBR·Evelyne KohliCarmen Garrido
Sep 24, 2020·Biochemical Pharmacology·Jonathan O RaynerPaul Dent

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