Cisplatin (DDP) is currently one of the most commonly used chemotherapeutic drugs for treating ovarian and lung cancer. However, resistance to cisplatin is common and it often leads to therapy failure. In addition, the precise mechanism of cisplatin resistance is still in its infancy. In this study, we demonstrated that the oxidative pentose phosphate pathway enzyme 6-phosphogluconate dehydrogenase (6PGD) promotes cisplatin resistance. We showed that cisplatin-resistant cancer cells (C13∗ and A549DDP), had higher levels of 6PGD compared to their cisplatin-sensitive counterparts (OV2008 and A549). Furthermore, ovarian and lung cancer patients with higher 6PGD levels have worse survival outcomes relative to patients with lower 6PGD expression. Interestingly, we found that the upregulation of 6PGD in cisplatin-resistant cells was due to the decreased expression of miR-206 and miR-613, which we found to target this enzyme. We further demonstrate that suppressing 6PGD using shRNA, inhibitor or miR-206/miR-613, either as single agents or in combination, could sensitize cisplatin-resistant cancer cells to cisplatin treatment and thereby improving the therapeutic efficacy of cisplatin. Taken together, our results suggest that 6PGD serves as a novel potential target to overcome cisplatin resistance.

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Fibroblast growth factor receptors (FGFrs) have been implicated in the malignant transformation and chemoresistance of epithelial ovarian cancer; however, the underlying molecular mechanisms are poorly understood. increased sialyltransferase activity that enhances protein sialylation is an important post-translational process promoting cancer progression and malignancy. in the present study, α2,6-sialyltransferase (ST6Gal-i) overexpression or knockdown cell lines were developed, and FGFr1 was examined to understand the effect of sialylation on migration and drug resistance, and the underlying mechanisms. it was identified that cells with ST6Gal-I overexpression had increased cell viability and migratory ability upon serum deprivation. Moreover, ST6Gal-i overexpression cells had strong resistance to paclitaxel, as demonstrated by low growth inhibition rate and cell apoptosis level. a mechanistic study showed that ST6Gal-i overexpression induced high α2,6-sialylation of FGFr1 and increased the expression of phospho-erK1/2 and phospho-focal adhesion kinase. Further study demonstrated that the FGFr1 inhibitor Pd173047 reduced cell viability and induced apoptosis; however, ST6Gal-i overexpression decreased the anticancer effect of Pd173047. in addition, ST6Gal-i overexpression attenuated the effect of adriamycin on cancer cells. collectively, these results suggested that FGFr1 sialylation plays an important role in cell migration and drug chemoresistance in ovarian cancer cells.

Ovarian cancer (OC) is the most lethal of all gynecologic malignancies with poor survival rates. Although surgical treatment and chemotherapy had advanced to improve survival, platinum-based chemoresistance remains a major hurdle in the clinical treatment of OC. The search for novel active ingredients for the treatment of drug-resistant OC is urgently needed. Here, we demonstrated that icaritin, the main active ingredient derived from the traditional Chinese herb Epimedium genus, significantly suppressed the proliferation, migration, and invasion of both drug-susceptible and cisplatin-resistant OC cells in vitro. Mechanistically, icaritin at 20 μM significantly inhibited the phosphorylation of Akt and mTOR, as well as decreased the expression of vimentin and increased the expression of E-cadherin. Our data indicate that icaritin, a prenylated flavonoid natural product, could serve as a potential inhibitor of cisplatin-resistant OC by inhibiting the Akt/mTOR signaling pathway.