Inhibition of 6-Phosphogluconate Dehydrogenase Reverses Epirubicin Resistance Through Metabolic Reprograming in Triple-Negative Breast Cancer Cells

At present, chemotherapy is the most effective strategy for treating triple-negative breast cancer (TNBC), but its efficacy was limited by the development of chemo-resistance. The exact mechanism of chemoresistance still remains unclear. This study aims to examine whether 6-phosphogluconate dehydrogenase (6PGD), a key enzyme in the oxidative pentose phosphate pathway (PPP), could promote the resistance of TNBC cells to epirubicin. A TNBC epirubicin-resistant cell line was developed by increasing concentration and the effectiveness was tested. The expression and knockdown efficiency of 6PGD were further validated by performing quantitative real-time PCR (qPCR) and Western blot. The effects of 6PGD on parental and drug-resistant TNBC cell lines were verified based on proliferation and apoptosis experiments. Finally, nicotinamide adenine dinucleotide phosphate (NADPH) and lactate quantitative experiments were performed to examine the mechanism of 6PGD in promoting drug resistance. Epirubicin-resistant cancer cells exhibited a higher level of 6PGD in contrast to epirubicin-sensitive cells. In addition, 6PGD inhibited by genetic and pharmacological approaches significantly suppressed the growth and survival of both epirubicin-sensitive and epirubicin-resisteant TNBC cells. It should be noted that 6PGD inhibition sensitized epirubicin-resistant TNBC cells to epirubicin treatment. Moreover, it was also found that the levels of NADPH and lactate increased in epirubicin-resistant TNBC cells but decreased in response to 6PGD inhibition. The present results indicated that 6PGD inhibition disrupted metabolic reprogramming in epirubicin-resistant TNBC cells. Our work demonstrated that 6PGD inhibition reversed the resistance of TNBC cells to epirubicin, providing an alternative therapeutic choice to tackle the challenge of epirubicin resistance in TNBC treatment.