Oroxylin A inhibits Kaposi's sarcoma‐associated herpes virus (KSHV) vIL‐6–mediated lymphatic reprogramming of vascular endothelial cells through modulating PPARγ/Prox1 axis

Abstract

Background and purpose Kaposi's sarcoma–associated herpes virus (KSHV) vIL‐6 is sufficient to induce lymphatic reprogramming of vascular endothelial cells, which is a key event in Kaposi's sarcoma (KS) development. This study was aimed to investigate the effect of Chinese herb oroxylin A on lymphatic reprogramming and neovascularization by KSHV vIL‐6 in vitro and in vivo. Methods The lymphatic‐phenotype endothelial cell line was generated by lentiviral KSHV vIL‐6 infection. Cell viability and apoptosis were determined by MTT assay or flow cytometry with annexin V/propidium iodide staining. Migration, invasion, and neovascularization of the vIL‐6‐expressing lymphatic‐phenotype endothelial cells were determined by wound healing assay, transwell chamber assay, microtubule formation assay, and chick chorioallantoic membrane assay, respectively. Quantitative polymerase chain reaction and Western blot analysis were used to test the expression of Prox1, VEGFR3, podoplanin, LYVE‐1, and PPARγ in cells. Co‐localization of Prox1 and PPARγ was determined by immunofluorescence. Ubiquitination of Prox1 was detected by in vivo ubiquitination assay. Results The lymphatic‐phenotype endothelial cell line expressing KSHV vIL‐6 was successfully generated. Oroxylin A induced cellular invasion abrogation, apoptosis induction, and neovascularization inhibition of the vIL‐6‐expressing endothelial cells. Mechanically, oroxylin A elevated PPARγ expression, which in turn interacted with and facilitated Prox1 to undergo ubiquitinational degradation, and subsequently leads to VEGFR3, LYVE‐1, and podoplanin reduction. Conclusion Through modulating PPARγ/Prox1 axis, oroxylin A inhibits lymphatic reprogramming and neovascularization of KSHV vIL‐6. Thus, oroxylin A may serve as a candidate for the treatment of KS as well as other aggressive angiomas.

Oroxylin A: A Promising Flavonoid for Prevention and Treatment of Chronic Diseases

“…Apparently, OA regulates the expression of multiple proteins, such as transforming growth factor beta (TGF-β), nuclear factor E2-related factor 2 (Nrf2), mitofusin 2 (Mfn2), angiopoietin 2 (Ang-2), vascular endothelial growth factor (VEGF), glutathione (GSH), B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), caspase -3, -8 and -9, sirtuin 3 (SIRT3), alpha-smooth muscle actin (α-SMA), etc., [ 75 , 76 , 77 , 78 , 79 ]. The proteomic screening of cancer cells treated with OA has revealed that it downregulates several factors, such as mitochondrial uncoupling protein 2 (UCP2), MMP-2, MMP-9, PKM2, superoxide dismutase 2 (SOD2), hypoxia inducible factor 1 alpha (HIF-1α), and PROX1 [ 62 , 80 , 81 ].…”

Human Gammaherpesvirus 8 Oncogenes Associated with Kaposi’s Sarcoma

“…Other therapies and their respective therapeutic targets in signaling pathways modulated by KSHV oncoproteins, such as vIL-6 [128], have been described. Oroxylin A inhibits vIL-6-mediated lymphatic reprogramming of vascular endothelial cells through modulating PPARγ/Prox1 axis.…”

“…Oroxylin A inhibits vIL-6-mediated lymphatic reprogramming of vascular endothelial cells through modulating PPARγ/Prox1 axis. Thus, this therapy may serve as a candidate for the treatment of KS [128].…”

PPARG Could Work as a Valid Therapeutic Strategy for the Treatment of Lung Squamous Cell Carcinoma

“…Specifically, PPARG counter-regulated 12 molecules that were upregulated or downregulated by LSCC ( Figure 2). The expression levels of eight LSCC markers (XIAP, UBE2D1, SKP2, ACKR3, MI21, HOXA10, STAT1, and PDPN) were significantly upregulated in LSCC patients [13][14][15][16][17][18][19][20] and were downregulated by PPARG [21][22][23][24][25][26][27][28]. On the other hand, PPARG could activate multiple genes [29][30][31][32][33] inhibited by LSCC [34][35][36][37][38], including MIR 223, PTEN, ANGPT1, CYP2A6, and FOXA2.…”