Differential effects of thymoquinone on lysophosphatidic acid-induced oncogenic pathways in ovarian cancer cells

Abstract

Thymoquinone, a therapeutic phytochemical derived from Nigella sativa, has been shown to have a potent anticancer activity. However, it has been identified that the tumor microenvironment (TME) can attenuate the anticancer effects of thymoquinone (TQ) in ovarian cancer. Lysophosphatidic acid (LPA), a lipid growth factor present in high concentration in the TME of ovarian cancer, has been shown to regulate multiple oncogenic pathways in ovarian cancer. Taking account of the crucial role of LPA in the genesis and progression of ovarian cancer, the present study is focused on assessing the efficacy of TQ in inhibiting LPA-stimulated oncogenic pathways in ovarian cancer cells. Our results indicate that TQ is unable to attenuate LPA-stimulated proliferation or metabolic reprogramming in ovarian cancer cells. However, TQ potently inhibits the basal as well as LPA-stimulated migratory responses of the ovarian cancer cells. Furthermore, TQ abrogates the invasive migration of ovarian cancer cells induced by Gαi2, through which LPA stimulates cell migration. TQ also attenuates the activation of JNK, Src, and FAK, the downstream signaling nodes of LPA-LPAR-Gαi2 signaling pathway. In addition to establishing the differential effects of TQ in ovarian cancer cells, our results unravel the antitherapeutic role of LPA in the ovarian cancer TME could override the inhibitory effects of TQ on cell proliferation and metabolic reprogramming of ovarian cancer cells. More importantly, the concomitant finding that TQ could still sustain its inhibitory effect on LPA-stimulated invasive cell migration, points to its potential use as a response-specific therapeutic agent in ovarian cancer.

Chemopreventive and Anticancer Effects of Thymoquinone: Cellular and Molecular Targets

“…The observed attenuation of the therapeutic activity of TQ has been attributed to "microenvironmental effects". This is further substantiated by the observations that TQ could synergize with the pro-oncogenic activity of lysophosphatidic acid, which is present in ovarian cancer tumor microenvironment [165]. Specifically, TQ has been demonstrated to augment lysophosphatidic acid-induced glycolytic shift in ovarian cancer cells.…”

Thymoquinone, as a Novel Therapeutic Candidate of Cancers

“…Ten µM of TQ suppressed the invasion and migration of ovarian cells stimulated by lysophosphatidic acid (LPA), a growth factor presents in the tumor microenvironment (TME), besides inhibiting the downstream targets of LPA, such as JNK, Src, and FAK [ 95 ]. TQ (6 μg/mL) has reduced the permeability of plasma and mitochondrial membrane in the Caov-3 ovarian cancer cell line and decreased the nuclear area with a notable inhibition for both Bcl-2 and Bax, in addition to triggering the oxidative stress and increasing the apoptosis in ovarian cancer [ 14 ].…”

The Potential of Centella asiatica Herb and Cyperus rotundus L. Rhizomes Extract as a Chemoprevention Agent for Lung Cancer

“…The flavonoid content has an antiproliferation effect [22], and the phenolic acid content repairs DNA damage, cell proliferation, apoptosis, and invasion [7], [23]. The content of alkaloids can inhibit the proliferation and induction of apoptosis [24]. The tannin content has several pharmacological effects, including antioxidant and anti-free radicals and antimicrobial, anti-cancer, anti-nutritional, and cardioprotective effects [4].…”