Ginsenoside 20(S)-Rg3 suppresses ovarian cancer migration via hypoxia-inducible factor 1 alpha and nuclear factor-kappa B signals

Abstract

Hypoxia-inducible factor 1 is believed to play a prominent role in the survival and developing progress of cancers. As a result, inhibiting α subunit of hypoxia-inducible factor 1 represents an attractive strategy against tumor. Although hypoxia-inducible factor 1α is a hypoxia-regulated subunit, increasing evidence indicates that hypoxia-inducible factor 1α could stable expression under normoxic conditions, regulated by non-hypoxia-mediated mechanisms. However, there are few strategies to target hypoxia-inducible factor 1α under normoxic conditions. Here, we report that ginsenoside 20(S)-Rg3, one of the main active ingredients in red ginseng, restrains hypoxia-inducible factor 1α expression under normal oxygen levels in human ovarian cancer cell lines, SKOV3 and 3AO, which leads to potently inhibits migration of ovarian cancer in vitro and in vivo. 20(S)-Rg3 could decrease the expression of hypoxia-inducible factor 1α by upregulation of prolyl hydroxylase domain protein 1 to promoting hypoxia-inducible factor 1α ubiquitin-proteasome degradation under normal oxygen levels. Furthermore, 20(S)-Rg3 could attenuate the expression of nuclear factor-κ B, which may be another possible mechanism for 20(S)-Rg3 to block ovarian cancer migration. Taken together, our study suggests that 20(S)-Rg3 is a strong inhibitor of hypoxia-inducible factor 1α, which may provide a novel agent for future treatments for ovarian cancer.

Antitumor effects and molecular mechanisms of action of natural products in ovarian cancer (Review)

“…Liu et al (75) reported that ginsenoside 20(S)-Rg3 decreased the expression of HIF-1α by stimulating the ubiquitin-proteasome pathway, and inhibited EMT process, which was essential for metastasis (75). They also revealed that ginsenoside 20(S)-Rg3 upregulated prolyl hydroxylase domain protein 1 to cause degradation of HIF-1α under the conditions of normal oxygen (76). Furthermore, ginsenoside Rb1 inhibited hypoxia-induced EMT by downregulating miR-25 in ovarian cancer cells, which abrogated the suppression of miR-25 on the expression of EP300 (a transcriptional activator of E-cadherin) and E-cadherin (an essential molecule for adhesion between epithelial cells), thereby leading to an anti-metastatic effect (77).…”

Naturally occurring anti-cancer compounds: shining from Chinese herbal medicine

“…In recent years, the potential anti-cancer mechanisms of ginsenoside Rg3 have been demonstrated in various cancer models, which include the inhibition of cell proliferation and induction of apoptosis via down-regulating PI3K/Akt, and activation of caspase-3 and -9 and Bcl-2 family proteins [234,252], induction of cell cycle arrest by regulating CDK pathway [240], inhibition of metastasis through reducing the expressions of aquaporin 1, C-X-C chemokine receptor type 4 (CXCR4) and hypoxia-inducible factor 1α (HIF-1α) [253][254][255]. Moreover, 20(S)-ginsenoside Rh2 is shown to bind to recombinant and intracellular annexin A2 directly, and this inhibits the interaction between annexin A2 and NF-κB p50 subunit, which decreases NF-κB activation [256].…”

Phytoadaptogens in the Tumours Biotherapy and Geriatrics (Part 2)

“…В современных исследованиях, посвященных проблемам онкологии, большое внимание уделяется механизмам регуляции активности эукариотического фактора транскрипции NF-κB, а также фактора Обзоры литературы транскрипции активатора протеина 1 (АР-1), которые ответственны за c-jun, c-fos и другую онкогенную трансактивацию [17][18][19]. Многие авторы полагают, что противоопухолевая активность ФА, в том числе экстракта женьшеня, его полисахаридов, гинзенозидов (Rb1, Rc, Re, Rg1, Rg3 и IH-901), их метаболитов (образующихся в результате жизнедеятельности бактерий кишечника) опосредована подавлением активации факторов транскрипции (NF-κB и АР-1), а также экспрессии циклооксигеназы 2-го типа.…”