Programmed death ligand‐1 regulates angiogenesis and metastasis by participating in the c‐JUN/VEGFR2 signaling axis in ovarian cancer

Abstract

Background Although programmed cell death‐ligand 1 (PD‐L1) plays a well‐known function in immune checkpoint response by interacting with programmed cell death‐1 (PD‐1), the cell‐intrinsic role of PD‐L1 in tumors is still unclear. Here, we explored the molecular regulatory mechanism of PD‐L1 in the progression and metastasis of ovarian cancer. Methods Immunohistochemistry of benign tissues and ovarian cancer samples was performed, followed by migration, invasion, and angiogenesis assays in PD‐L1‐knockdown ovarian cancer cells. Immunoprecipitation, mass spectrometry, and chromatin immunoprecipitation were conducted along with zebrafish and mouse experiments to explore the specific functions and mechanisms of PD‐L1 in ovarian cancer. Results Our results showed that PD‐L1 induced angiogenesis, which further promoted cell migration and invasion in vitro and in vivo of ovarian cancer. Mechanistically, PD‐L1 was identified to directly interact with vascular endothelial growth factor receptor‐2 (VEGFR2) and then activated the FAK/AKT pathway, which further induced angiogenesis and tumor progression, leading to poor prognosis of ovarian cancer patients. Meanwhile, PD‐L1 was found to be regulated by the oncogenic transcription factor c‐JUN at the transcriptional level, which enhanced the expression of PD‐L1 in ovarian cancer. Furthermore, we demonstrated that PD‐L1 inhibitor durvalumab, combined with the antiangiogenic drug, apatinib, could enhance the effect of anti‐angiogenesis and the inhibition of cell migration and invasion. Conclusion Our results demonstrated that PD‐L1 promoted the angiogenesis and metastasis of ovarian cancer by participating in the c‐JUN/VEGFR2 signaling axis, suggesting that the combination of PD‐L1 inhibitor and antiangiogenic drugs may be considered as a potential therapeutic approach for ovarian cancer patients.

Apatinib triggers autophagic and apoptotic cell death via VEGFR2/STAT3/PD-L1 and ROS/Nrf2/p62 signaling in lung cancer

“…The cytotoxic effects of apatinib might lead to the reduction of total VEGFR2 in NSCLC cells. It is reported that multiple signaling pathways and molecules might be involved in the regulation of VEGFR2 expression [46][47][48]. Our previous study also indicated that apatinib suppressed lung cancer stem-like properties by inactivation of β-catenin signaling, which might further lead to the downregulation of VEGF and its receptor VEGFR2 [49].…”

Anti-Tumor Effect of Apatinib and Relevant Mechanisms in Liposarcoma

“…reported that PD-L1 promotes angiogenesis in ovarian cancer through the c-Jun/VEGFR-2 signaling axis. Furthermore, a combination of the PD-L1 inhibitor durvalumab plus Apatinib enhanced the anti-angiogenesis effect and inhibition of cell migration and invasion ( 38 ). These findings suggested that synergy between Apatinib and immunosuppressants does not merely involve a single pathway and that Apatinib may work synergistically with immunosuppressive agents in the treatment of retroperitoneal liposarcoma.…”

The Mechanism of Stimulating and Mobilizing the Immune System Enhancing the Anti-Tumor Immunity

“…Autophagy is beneficial to normal cells, but in tumors, it helps malignant cells adjust and adapt to adverse conditions, allowing them to develop and continue to grow. In addition, the PD-1/PD-L1 signaling pathway plays a key role in tumor function and survival (55,56). Autophagy is influenced by the PD-L1 ligand.…”