Thymoquinone Suppresses Migration of Human Renal Carcinoma Caki-1 Cells through Inhibition of the PGE₂-Mediated Activation of the EP2 Receptor Pathway

Abstract

Renal cell carcinoma (RCC) is likely to metastasize to other organs, and is often resistant to conventional chemotherapies. Thymoquinone (TQ), a phytochemical derived from the seeds of Nigella sativa , has been shown to inhibit migration and metastasis in various cancers. In this study, we assessed the effect of TQ on the migratory activity of human RCC Caki-1 cells. We found that treatment with TQ reduced the proteolytic activity of matrix metalloproteinase-9 (MMP-9) in Caki-1 cells. TQ significantly repressed prostaglandin E 2 (PGE 2 ) production, its EP2 receptor expression as well as the activation of Akt and p38, the well-known upstream signal proteins of MMP-9. In addition, treatment with butaprost, a PGE 2 agonist, also induced MMP-9 activity and migration/invasion in Caki-1 cells. Moreover, pharmacological inhibitors of PI3K/Akt and p38 remarkably attenuated butaprost-induced Caki-1 cell migration and invasion, implying that activation of PI3K/Akt and p38 is a bridge between the PGE 2 -EP2 axis and MMP-9-dependent migration and invasion. Taken together, these data suggest that TQ is a promising anti-metastatic drug to treat advanced and metastatic RCC.

Thymoquinone Alterations of the Apoptotic Gene Expressions and Cell Cycle Arrest in Genetically Distinct Triple-Negative Breast Cancer Cells

“…Targeting invasion and migration are especially essential for malignancies that currently lack specific treatments, such as TNBC [ 52 ]. Several studies have reported the role of TQ in cancer cell migration [ 53 , 54 , 55 , 56 ]. The authors noted that TQ inhibits the migration and invasion of prostate cancer [ 57 ] and BC [ 58 ] in a concentration-dependent manner.…”

Renal cancer: signaling pathways and advances in targeted therapies

“… 45 Natural compounds, such as shikonin and thymoquinone (TQ), have also been shown to exert anti‐RCC effects by modulating the PI3K/AKT signaling pathway. 46 , 47 Shikonin inhibits RCC cell proliferation in a dose‐dependent manner and induces apoptosis by activating the Ras/MAPK and PI3K/AKT signaling pathways. 46 Similarly, TQ inhibits RCC cell migration by suppressing the activation of the prostaglandin E2 ( PGE2 )‐mediated EP2 receptor– PI3K/AKT axis.…”

“… 46 Similarly, TQ inhibits RCC cell migration by suppressing the activation of the prostaglandin E2 ( PGE2 )‐mediated EP2 receptor– PI3K/AKT axis. 47 …”

Lipids as Targets for Renal Cell Carcinoma Therapy

“…Despite these ambiguities, it is generally accepted that COX-2 exerts a pleiotropic and multifaceted role in carcinogenesis and cancer cell resistance to chemo- and radiotherapy [ 137 ]. The exact mechanisms of COX-2 contribution to RCC are under investigation but involve increased cell proliferation, angiogenesis, matrix metalloproteinase (MMP)-2 expression, invasiveness, and metastasis [ 134 , 138 ].…”

“…Still, in vitro and in vivo data show an association of a COX-2/PGE 2 /EP axis with invasion and metastasis. This is because in addition to the overproduction of PGE 2 , the aberrant expression of its receptors can also amplify PGE 2 signaling, which can facilitate cancer promotion and metastasis [ 138 ]. In particular, EP 2 and EP 4 may play important roles in the malignant behavior of RCC.…”