Adipocyte-rich microenvironment promotes chemoresistance via upregulation of peroxisome proliferator-activated receptor gamma/ABCG2 in epithelial ovarian cancer

The effects of adipocyte-rich microenvironment (ARM) on chemoresistance have garnered increasing interest. Ovarian cancer (OVCA) is a representative adipocyte-rich associated cancer. In the present study, epithelial OVCA (EOC) was used to investigate the influence of ARM on chemoresistance with the aim of identifying novel targets and developing novel strategies to reduce chemoresistance. Bioinformatics analysis was used to explore the effects of ARM-associated mechanisms contributing to chemoresistance and treated EOC cells, primarily OVCAR3 cells, with human adipose tissue extracts (HATES) from the peritumoral adipose tissue of patients were used to mimic ARM in vitro. Specifically, the peroxisome proliferator-activated receptor gamma (PPAR gamma) antagonist GW9662 and the ABC transporter G family member 2 (ABCG2) inhibitor KO143, were used to determine the underlying mechanisms. Next, the effect of HATES on the expression of PPAR gamma and ABCG2 in OVCAR3 cells treated with cisplatin (DDP) and paclitaxel (PTX) was determined. Additionally, the association between PPAR gamma, ABCG2 and chemoresistance in EOC specimens was assessed. To evaluate the effect of inhibiting PPAR gamma, using DDP, a nude mouse model injected with OVCAR3-shPPAR gamma cells and a C57BL/6 model injected with ID8 cells treated with GW9662 were established. Finally, the factors within ARM that contributed to the mechanism were determined. It was found that HATES promoted chemoresistance by increasing ABCG2 expression via PPAR gamma. Expression of PPAR gamma/ABCG2 was related to chemoresistance in EOC clinical specimens. GW9662 or knockdown of PPAR gamma improved the efficacy of chemotherapy in mice. Finally, angiogenin and oleic acid played key roles in HATES in the upregulation of PPAR gamma. The present study showed that the introduction of ARM-educated PPAR gamma attenuated chemoresistance in EOC, highlighting a potentially novel therapeutic adjuvant to chemotherapy and shedding light on a means of improving the efficacy of chemotherapy from the perspective of ARM.