Despite myriad challenges, clinicians see room for progress.
Image credit: Shutterstock/David Tadevosian.
Edited by Tak W. Mak, The Campbell Family Institute for Breast Cancer Research at Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada, and approved December 24, 2015 (received for review May 5, 2015)
Significance
Excessive accumulation of oxidative stress is harmful to cancer cells. Our study demonstrates the important roles of a pentose phosphate pathway (PPP) enzyme, transketolase (TKT), in redox homeostasis in cancer development. We highlight the clinical relevance of TKT expression in cancers. We also show that TKT overexpression in cancer cells is a response of Nuclear Factor, Erythroid 2-Like 2 (NRF2) activation, a sensor to cellular oxidative stress. TKT locates at an important position that connects PPP with glycolysis to affect production of antioxidant NADPH. Our preclinical study shows that targeting TKT leads to elevation of oxidative stress, making cancer cells more vulnerable to therapeutic treatment, such as Sorafenib. Using TKT as an example, our study suggests that targeting enzymes for antioxidant production represents a direction for cancer treatment.
Abstract
Cancer cells experience an increase in oxidative stress. The pentose phosphate pathway (PPP) is a major biochemical pathway that generates antioxidant NADPH. Here, we show that transketolase (TKT), an enzyme in the PPP, is required for cancer growth because of its ability to affect the production of NAPDH to counteract oxidative stress. We show that TKT expression is tightly regulated by the Nuclear Factor, Erythroid 2-Like 2 (NRF2)/Kelch-Like ECH-Associated Protein 1 (KEAP1)/BTB and CNC Homolog 1 (BACH1) oxidative stress sensor pathway in cancers. Disturbing the redox homeostasis of cancer cells by genetic knockdown or pharmacologic inhibition of TKT sensitizes cancer cells to existing targeted therapy (Sorafenib). Our study strengthens the notion that antioxidants are beneficial to cancer growth and highlights the therapeutic benefits of targeting pathways that generate antioxidants.
Footnotes
- ↵1To whom correspondence may be addressed. Email: iolng{at}hku.hk or carmencl{at}pathology.hku.hk.
Author contributions: I.M.-J.X., C.C.-L.W., and I.O.-L.N. designed research; I.M.-J.X., R.K.-H.L., S.-H.L., A.P.-W.T., D.K.-C.C., H.-Y.K., C.-T.L., C.-M.W., and C.C.-L.W. performed research; I.M.-J.X., S.-H.L., C.-T.L., C.-M.W., Z.C., C.C.-L.W., and I.O.-L.N. contributed new reagents/analytic tools; I.M.-J.X., S.-H.L., Z.C., C.C.-L.W., and I.O.-L.N. analyzed data; and I.M.-J.X., C.C.-L.W., and I.O.-L.N. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1508779113/-/DCSupplemental.
Freely available online through the PNAS open access option.
http://www.pnas.org/preview_site/misc/userlicense.xhtmlTKT drives cancer development
Sign up for Article Alerts
Jump to section
You May Also be Interested in
Better explicating the strengths and shortcomings of these models will help refine projections and improve transparency in the years ahead.
Image credit: Witsawat.S.
Using CRISPR, researchers showed that a region some used to label “junk DNA” has a major role in a rare genetic disorder.
Image credit: Nathan Devery.
Mara Reed and Michael Manga explore why Yellowstone's Steamboat Geyser resumed erupting in 2018.
Some songbird parents might improve their own fitness by manipulating their offspring into leaving the nest early, at the cost of fledgling survival, a study finds.
Image credit: Gil Eckrich (photographer).