G6PD inhibition sensitizes ovarian cancer cells to oxidative stress in the metastatic omental microenvironment
Shree Bose, Qiang Huang, Yunhan Ma, Lihua Wang, Grecia O. Rivera, Yunxin Ouyang, Regina S. Whitaker, Rebecca A. Gibson, Christopher D. Kontos, Andrew Berchuck, Rebecca A. Previs, Xiling Shen
Abstract
Ovarian cancer (OC) is the most lethal gynecological malignancy, with aggressive metastatic disease responsible for the majority of OC-related deaths. In particular, OC tumors preferentially metastasize to and proliferate rapidly in the omentum. Here, we show that metastatic OC cells experience increased oxidative stress in the omental microenvironment. Metabolic reprogramming, including upregulation of the pentose phosphate pathway (PPP), a key cellular redox homeostasis mechanism, allows OC cells to compensate for this challenge. Inhibition of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the PPP, reduces tumor burden in pre-clinical models of OC, suggesting that this adaptive metabolic dependency is important for OC omental metastasis.