Inhibition of the hexosamine biosynthesis pathway potentiates cisplatin cytotoxicity by decreasing BiP expression in non-small-cell lung cancer cells

Molecular Carcinogenesis
Wenshu ChenYong Lin

Abstract

Platinum anticancer agents are essential components in chemotherapeutic regimens for non-small-cell lung cancer (NSCLC) patients ineligible for targeted therapy. However, platinum-based regimens have reached a plateau of therapeutic efficacy; therefore, it is critical to implement novel approaches for improvement. The hexosamine biosynthesis pathway (HBP), which produces amino-sugar N-acetyl-glucosamine for protein glycosylation, is important for protein function and cell survival. Here we show a beneficial effect by the combination of cisplatin with HBP inhibition. Expression of glutamine:fructose-6-phosphate amidotransferase (GFAT), the rate-limiting enzyme of HBP, was increased in NSCLC cell lines and tissues. Pharmacological inhibition of GFAT activity or knockdown of GFATimpaired cell proliferation and exerted synergistic or additive cytotoxicity to the cells treated with cisplatin. Mechanistically, GFAT positively regulated the expression of binding immunoglobulin protein (BiP; also known as glucose-regulated protein 78, GRP78), an endoplasmic reticulum chaperone involved in unfolded protein response (UPR). Suppressing GFAT activity resulted in downregulation of BiP that activated inositol-requiring enzyme 1α, a sensor pr...Continue Reading

References

Aug 22, 1975·Annals of the New York Academy of Sciences·S Tsuiki, T Miyagi
Mar 29, 2001·The Journal of Biological Chemistry·K KawanakaJ O Holloszy
Jun 5, 2002·Biochimica Et Biophysica Acta·Sławomir Milewski
Feb 18, 2003·The Journal of Biological Chemistry·Makoto HiromuraAnny Usheva
Jun 20, 2006·Biochimica Et Biophysica Acta·Natasha E Zachara, Gerald W Hart
Aug 4, 2009·Biochimica Et Biophysica Acta·John A HanoverDona C Love
Dec 3, 2009·American Journal of Physiology. Endocrinology and Metabolism·Andrew T SageGeoff H Werstuck
May 15, 2010·Trends in Biochemical Sciences·C SlawsonG W Hart
May 22, 2010·Seminars in Cell & Developmental Biology·Dona C LoveJohn A Hanover
Dec 1, 2011·Physiological Genomics·Ida G LundeCathrine R Carlson
Dec 19, 2012·Chemical Society Reviews·Partha S BanerjeeJin Won Cho
Feb 15, 2013·Proceedings of the National Academy of Sciences of the United States of America·Fabienne GuillaumondSophie Vasseur
Jul 16, 2013·Biochimica Et Biophysica Acta·Renata Sano, John C Reed
Nov 30, 2013·Pharmacology & Therapeutics·Sujith Dassanayaka, Steven P Jones
Dec 10, 2013·The Journal of Clinical Investigation·Yasuhito OnoderaMina J Bissell
May 14, 2014·Proceedings of the National Academy of Sciences of the United States of America·Behzad Kharabi MasoulehMarkus Müschen
May 24, 2014·Cell Death & Disease·T Kosakowska-CholodyJ K Acharya
Nov 17, 2014·Cytotechnology·Nizar M MhaidatSulaiman Swaidan
Apr 1, 2015·The Journal of Cell Biology·Michelle R Bond, John A Hanover
Jun 21, 2016·Current Opinion in Chemical Biology·Stéphan Hardivillé, Gerald W Hart
Jun 28, 2016·Nature Reviews. Immunology·Joep GrootjansRichard S Blumberg
Dec 21, 2016·Scientific Reports·Caiting YangJianxin Gu
Mar 21, 2017·Oncogenesis·A Vasconcelos-Dos-SantosA R Todeschini
Apr 14, 2017·Journal of the National Comprehensive Cancer Network : JNCCN·David S EttingerMiranda Hughes
Sep 8, 2017·Scientific Reports·Sudjit LuanpitpongSurapol Issaragrisil

❮ Previous
Next ❯

Citations

May 30, 2020·International Journal of Oncology·Daniel L PouliquenCatherine Guette
Jan 9, 2021·Chemical Reviews·Junfeng MaGerald W Hart
Mar 22, 2021·Journal of Translational Medicine·Shengkai XiaQi Wang
Jun 17, 2021·Cellular and Molecular Life Sciences : CMLS·Abudureyimu TuerhongChen Liang
Jul 17, 2021·Carcinogenesis·Wenshu ChenSteven A Belinsky

❮ Previous
Next ❯

Related Concepts

Related Feeds

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis

Apoptosis in Cancer

Apoptosis is an important mechanism in cancer. By evading apoptosis, tumors can continue to grow without regulation and metastasize systemically. Many therapies are evaluating the use of pro-apoptotic activation to eliminate cancer growth. Here is the latest research on apoptosis in cancer.