Antitumor Effects of Ursolic Acid through Mediating the Inhibition of STAT3/PD-L1 Signaling in Non-Small Cell Lung Cancer Cells

Abstract

Targeted therapy based on natural compounds is one of the best approaches against non-small cell lung cancer. Ursolic acid (UA), a pentacyclic triterpenoid derived from medicinal herbs, has anticancer activity. Studies on the molecular mechanism underlying UAʹs anticancer activity are ongoing. Here, we demonstrated UAʹs anticancer activity and the underlying signaling mechanisms. We used Western blotting and real-time quantitative polymerase chain reaction for molecular signaling analysis. We also used in vitro angiogenesis, wound healing, and invasion assays to study UAʹs anticancer activity. In addition, we used tumorsphere formation and chromatin immunoprecipitation assays for binding studies. The results showed that UA inhibited the proliferation of A549 and H460 cells in a concentration-dependent manner. UA exerted anticancer effects by inducing G0/G1 cell cycle arrest and apoptosis. It also inhibited tumor angiogenesis, migration, invasion, and tumorsphere formation. The molecular mechanism underlying UA activity involves UAʹs binding to epidermal growth factor receptor (EGFR), reducing the level of phospho-EGFR, and thus inhibiting the downstream JAK2/STAT3 pathway. Furthermore, UA reduced the expressions of vascular endothelial growth factor (VEGF), metalloproteinases (MMPs) and programmed death ligand-1 (PD-L1), as well as the formation of STAT3/MMP2 and STAT3/PD-L1 complexes. Altogether, UA exhibits anticancer activities by inhibiting MMP2 and PD-L1 expression through EGFR/JAK2/STAT3 signaling.

The Anti-Cancer Effects of Red-Pigmented Foods: Biomarker Modulation and Mechanisms Underlying Cancer Progression

“…The anti-tumor activity of ursolic acid can be partly attributed to its binding to EGFR and subsequent down-regulation of phospho-EGFR and inhibition of the JAK2/STAT3 signaling pathway. In addition, ursolic acid reduces VEGF, MMP, and PD-L1 expression, as well as STAT3/MMP2 and STAT3/PD-L1 complex formation, observations reported in non-small cell lung cancer cells [105]. Conway et al noted that ursolic acid inhibited collective cell migration while promoting lysosome-associated cell death, outcomes that were JNK-dependent in glioblastoma multiforme cells [106].…”

“…Ursolic acid Apple peels ↑ sFRP4, sp1, Caveolin-1, Bax, p21, p53, Cyclin B1, Caspase-3, Caspase-8, Caspase-9, fibronectin-1, E-Cad, and LC3-II Gliolastoma [104], breast [100,101], intestinal [102], lung [103], colorectal [105], esophageal [106], and pancreatic [107] [111], breast [112,113], prostate [115], ovarian [114], colorectal [116,117], lung [118], gastric [56], and endometrial [119] cancer ↓ MMP-2, FAK, CDK1, PSA, TMPRSS2, TMEPA1, PI3K, Akt, Bcl-2, TS, RhoA, Rac1, JAK/STAT3, MAPK, and NFκB Quercetin Apple, chili pepper, blueberry, cherry, cranberry, black tea, and red wine ↑ p53 Liver [120,121], prostate [122,123], colon [123], leukemia [123], lymphoma [123], breast [123,124], pancreatic [125], lung [126],…”

Silibinin Regulates Tumor Progression and Tumorsphere Formation by Suppressing PD-L1 Expression in Non-Small Cell Lung Cancer (NSCLC) Cells

“…In addition, a high level of PD-L1 has been confirmed to appear on the surface of different cancer cells, including NSCLC, justifying that its expression facilitates cancer cells to escape immune response [ 18 ]. PI3K/AKT and JAK/STAT pathways play a vital role in the expression of PD-L1 in tumor cells which takes part in different cancer hallmarks [ 19 , 20 ]. The PD-1/PD-L1 inhibitory checkpoint suppresses antitumor immune responses [ 21 , 22 ].…”

Targeting Autophagy with Natural Compounds in Cancer: A Renewed Perspective from Molecular Mechanisms to Targeted Therapy

“…In addition, there is a secretion from the animal toad -Bufalin. Accumulating evidences have shown that natural compounds play an important role in the treatment of cancer, including inhibiting cancer cell proliferation and inducing apoptosis, as well as inhibiting cancer cell metastasis and angiogenesis (Liu et al, 2019a;Sun et al, 2019;Liu et al, 2020;Kang et al, 2021). More interestingly, in the treatment of tumors, multiple natural compounds are reported to exert therapeutic effect by targeting autophagy (Towers et al, 2020).…”