Induction of galectin-1 by TLR-dependent PI3K activation enhances epithelial-mesenchymal transition of metastatic ovarian cancer cells

Abstract

The expression of different toll-like receptors (TLRs) on tumor cells has been associated with disease aggressiveness, treatment resistance, and poor prognosis. The phosphatidylinositol 3-kinase (PI3K)/AKT pathway is considered critical for cancer cell survival and proliferation. Thus, we investigated the effect of TLR-stimulated PI3K activation on the epithelial-to-mesenchymal transition (EMT) of primary (Caov-3) and metastatic (SK‑OV‑3) epithelial ovarian cancer cell lines in this study. TLR engagement with various ligands promoted the expression of class IA PI3K (p110α, p110β, and p110δ) and increased the expression of mesenchymal markers (N-cadherin, Slug, Vimentin, Snail, α-SMA, and TCF) in SK‑OV‑3 cells. The migratory activity and secretion of EMT-related cytokines of SK‑OV‑3 were significantly higher compared to those of Caov-3 after activation with TLR agonist. Although the invasive capacity and production of EMT-related cytokines of LPS-stimulated SK‑OV‑3 cells were significantly suppressed by all pharmacological inhibitors of the p110 isoform, the Syk/Src-dependent p110β isoform prominently attenuated migration activity. In contrast, the production of IL-10 and galectin-1 was mainly affected by the p110δ isoform. Gene silencing of TLR4 and galectin-1 with siRNA decreased the expression of matrix metalloproteinase-2 (MMP2) and MMP9 and reduced mesenchymal markers in LPS-treated SK‑OV‑3 cells. This study demonstrated that TLR-mediated PI3K activation modulated the invasion and metastasis of ovarian cancer through the production of galectin-1, suggesting that inhibition of the p110 isoform is a promising therapeutic approach against metastatic ovarian cancer.

Galectins and Ovarian Cancer

“…Interestingly, the cisplatin-resistant ovarian cancer cells transfected with Gal-1 siRNA were more responsive to the negative effects of cisplatin than those transfected with the control siRNA. These findings [ 71 ], and those of others [ 55 , 69 , 70 , 76 ], suggest that if a targeted disruption of Gal-1 expression/function in tumor tissue or the immediate tumor microenvironment could be obtained, it may be a plausible therapeutic option for cisplatin-resistant ovarian cancer.…”

“…In a study by Park et al [ 76 ], they were investigating the differences in toll-like receptor (TLR) mediated phosphoinositol 3 kinase (PI3K) signaling activity in CAOV3 and SKOV3 ovarian cancer cell lines. The investigators had postulated that Gal-1 might be a promising candidate for downstream targeting of the TLR/PI3k mediated signaling pathway in metastatic ovarian cancer.…”

Melatonin, a toll‐like receptor inhibitor: Current status and future perspectives

“…Zhang et al, 2015). TLR-mediated PI3K activation modulates the invasion and metastasis of ovarian cancer through the production of galectin-1, suggesting that inhibition of the p110 isoform may be a promising therapeutic approach against metastatic ovarian cancer (Park, Chung, & Kim, 2017). Another study revealed that TLRs may be a target for treatment of ovarian cancer (Muccioli & Benencia, 2014 (2015) found that melatonin therapy reduced TLR2 levels, while it suppressed the ovarian cancer-associated increase in the levels of the following proteins: TLR4, MyD88, NF-kB p65, inhibitor of NFkB α (IkBα), IKK-α, TNF receptor-associated factor 6 (TRAF6), TRIF, IRF3, interferon β (IFN-β), tumor necrosis factor α (TNF-α), and interleukin (IL)-6.…”

TLR5/7-mediated PI3K activation triggers epithelial-mesenchymal transition of ovarian cancer cells through WAVE3-dependent mesothelin or OCT4/SOX2 expression

“…TLRs stimulation is functionally associated with tumor growth and progression (16). We also reported that TLR4-mediated TLR5/7-mediated PI3K activation triggers epithelial-mesenchymal transition of ovarian cancer cells through WAVE3-dependent mesothelin or OCT4/SOX2 expression PI3K activation controls the invasion and metastasis of ovarian cancer through the production of galectin-1 (17). However, the underlying mechanism and association of PI3K for inducing mesothelin in TLR5/7-activated ovarian cancer cells remains unclear.…”