Targeting the pentose phosphate pathway increases reactive oxygen species and induces apoptosis in thyroid cancer cells

Chien-Liang Liu; Yi-Chiung Hsu; Jie-Jen Lee; Ming-Jen Chen; Chi-Hsin Lin; Shih-Yuan Huang; Shih-Ping Cheng

doi:10.1016/j.mce.2019.110595

Targeting the pentose phosphate pathway increases reactive oxygen species and induces apoptosis in thyroid cancer cells

Mol Cell Endocrinol. 2020 Jan 1:499:110595. doi: 10.1016/j.mce.2019.110595. Epub 2019 Sep 26.

Authors

Chien-Liang Liu¹, Yi-Chiung Hsu², Jie-Jen Lee³, Ming-Jen Chen¹, Chi-Hsin Lin⁴, Shih-Yuan Huang⁵, Shih-Ping Cheng⁶

Affiliations

¹ Department of Surgery, MacKay Memorial Hospital and Mackay Medical College, Taipei, Taiwan, ROC; Department of Medical Research, MacKay Memorial Hospital, Taipei, Taiwan, ROC.
² Department of Biomedical Sciences and Engineering, National Central University, Taoyuan City,Taiwan, ROC.
³ Department of Surgery, MacKay Memorial Hospital and Mackay Medical College, Taipei, Taiwan, ROC.
⁴ Department of Medical Research, MacKay Memorial Hospital, Taipei, Taiwan, ROC; Department of Bioscience Technology, Chung Yuan Christian University, Taoyuan City, Taiwan, ROC.
⁵ Department of Medical Research, MacKay Memorial Hospital, Taipei, Taiwan, ROC.
⁶ Department of Surgery, MacKay Memorial Hospital and Mackay Medical College, Taipei, Taiwan, ROC; Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC. Electronic address: surg.mmh@gmail.com.

PMID: 31563469
DOI: 10.1016/j.mce.2019.110595

Abstract

The pentose phosphate pathway (PPP) plays an important role in the biosynthesis of ribonucleotide precursor and NADPH. Cancer cells frequently increase the flux of glucose into the PPP to support the anabolic demands and regulate oxidative stress. Consistently, metabolomic analyses indicate an upregulation of the PPP in thyroid cancer. In the present study, we found that the combination of glucose-6-phosphate dehydrogenase (G6PD) and transketolase inhibitors (6-aminonicotinamide and oxythiamine) exerted an additive or synergistic effect on cell growth inhibition in thyroid cancer cells. Targeting PPP significantly increased cellular reactive oxygen species (ROS) and induced endoplasmic reticulum (ER) stress and apoptosis. Suppressed cell viability could be partially rescued with treatment with the ROS scavenger or apoptosis inhibitor but not ER-stress inhibitor. Taken together, dual PPP blockade leads to pharmacologic additivity or synergism and causes ROS-mediated apoptosis in thyroid cancer cells.

Keywords: Apoptosis; Pentose phosphate pathway; Reactive oxygen species; Thyroid cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

6-Aminonicotinamide / pharmacology*
Cell Line, Tumor
Cell Survival / drug effects
Endoplasmic Reticulum Stress / drug effects
Gene Expression Regulation, Neoplastic / drug effects
Glucosephosphate Dehydrogenase
Humans
NADP / metabolism
Oxidative Stress / drug effects
Oxythiamine / pharmacology*
Pentose Phosphate Pathway / drug effects*
Reactive Oxygen Species / metabolism*
Thyroid Neoplasms / drug therapy
Thyroid Neoplasms / metabolism*

Substances

Reactive Oxygen Species
Oxythiamine
6-Aminonicotinamide
NADP
Glucosephosphate Dehydrogenase