Palmitic Acid-Activated GPRS/KLF7/CCL2 Pathway Contributes to the Crosstalk between Bone Marrow Adipocytes and Prostate Cancer

Obesity-induced abnormal bone marrow microenvironment is an important risk factor for bone metastasis of prostate cancer (PCa). This study was intended to investigate whether obesity-induced elevated palmitic acid (PA), the most abundant free fatty acids (FFAs), increased CCL2 through GPRs/KLF7 pathway in bone marrow adipocytes(BMA) to promote the growth and metastasis of PCa. In BALB/c nude mice, we found that the distribution of BMA in the bone marrow cavity of high fatty diet(HFD) mice were significantly higher than normal diet(ND) mice. More importantly, HFD-induced obesity promotes the KLF7/CCL2 expression of BMA and PCa cells growth in bone marrow cavity. In vitro, conditioned medium with elevated CCL2 obtained from BMA incubated with PA (CM-BMA-PA) was used to deal with PCa cell lines, and a significant increase in the proliferation, invasion, and migration ability was found in PC3 cells. KLF7 could strikingly increase the CCL2 expression and release levels of BMA. Moreover, GPR40/120 involved in PA-induced high KLF7/CCL2 levels of BMA to promote malignant progression of PC3 cells. In conclusion, PA-activated GPRs/KLF7/CCL2 pathway of BMA promotes the growth and metastasis of prostate cancer. Funding: This research was funded by the Natural Science Foundation of China (grant number 81760518), Xinjiang Production and Construction Corps Key Areas Innovation Team Project (grant number 2018CB002), the Scientific and Technological Research Project of Xinjiang Production and Construction Corps (grant number 2018AB018, 2021AB028), and Projects of Shihezi University (grant number ZZZC202017A, ZZZC201817A, GJHZ201703). Declaration of Interest: None to declare. Ethical Approval: All experiments involving mice were performed in accordance with the protocol approved by the Medical Ethics Committee at First Affiliated Hospital, Shihezi University School of Medicine (reference number: A2017-115-01).