Ginsenoside Rg3 Alleviates Cisplatin Resistance of Gastric Cancer Cells Through Inhibiting SOX2 and the PI3K/Akt/mTOR Signaling Axis by Up-Regulating miR-429

Abstract

Platinum-based cytotoxic chemotherapy is considered the standard treatment for advanced gastric cancer (GC). However, cisplatin chemoresistance often occurs with the mechanisms being not well clarified, which results in the cancer recurrence and poor survival. Ginsenoside Rg3, isolated from the Chinese Herb Panax Ginseng, is recognized as an anti-cancer agent. Herein, we aimed to reveal whether Ginsenoside Rg3 alleviates cisplatin resistance and sensitizes GC cells to cisplatin-induced apoptosis, and draw out the underlying molecular mechanism in cisplatin-resistant GC cells. The lower expression of miR-429 was found in AGSR-CDDP cells; it was also in association with cisplatin-resistance in GC cells and expression of which was restored following Ginsenoside Rg3 treatment. We also demonstrated that miR-429 made a contribution toward chemosensitivity in GC cells partly through SOX2 regulation. SOX2 was found to contribute to developing platinum resistance and was an authentic target for miR-429 in AGSR-CDDP cells. Importantly, enforced expression of SOX2 with a pcDNA3-SOX2 construct lacking the 3′-UTR miRNA binding site diminished the cytotoxic effects of miR-429 in AGSR-CDDP cells. We demonstrated that Ginsenoside Rg3 enhanced chemosensitivity in AGSR-CDDP GC cells, at least in part, through up-regulating miR-429, thereby targeting SOX2 and modulating downstream PI3K/AKT/mTOR signaling. Ginsenoside Rg3 was also found to regulate apoptosis-related genes via miR-429 in cisplatin-resistant GC cells. Ginsenoside Rg3 treatment significantly suppressed the migration rate of AGSR-CDDP GC cells, while following transfection with anti-miR-429, the anti-migratory effects of Ginsenoside Rg3 was partially abolished. This data suggested that Ginsenoside Rg3 may impede the chemoresistance and migration of GC cells mainly mediated through miR-429. We concluded that miR-429-regulated SOX2 expression was one of the main mechanisms by which Ginsenoside Rg3 dramatically promoted its anticancer effects on cisplatin-resistant GC cells. We also underscored a supporting model in which miR-429 adjusted PI3K/AKT/mTOR signaling by regulating SOX2 in cisplatin-resistant GC cells.

Natural Products in Preventing Tumor Drug Resistance and Related Signaling Pathways

“…The use of ginsenoside Rg3 may contribute to reducing toxicity and improving chemosensitivity in cancer combination therapy [ 204 ]. It was found that ginsenoside Rg3 reduced cisplatin resistance by upregulating miR-429 to inhibit the SOX2 and PI3K/Akt/mTOR signaling axes in gastric cancer treatment [ 30 ]. In pancreatic cancer treatment, ginsenoside Rg3 regulated the survival of pancreatic cancer cells via the PI3K/Akt/mTOR pathway [ 205 ].…”

“…For example, matrine can improve the sensitivity of resistant cancer cells to chemotherapeutic drugs by reactivating apoptosis and inhibiting drug efflux [ 26 ]; Tetrandrine can fight the multiple-drug resistance (MDR) of cancer cells by downregulating the expression of ABCB1 transporters [ 27 ]; quercetin can reverse the resistance of paclitaxel-resistant prostate cancer cells in vitro by reversing activation of the androgen receptor and PI3K/Akt signaling [ 28 ]. Osthole reverses the chemotherapeutic resistance of cisplatin-resistant cervical cancer cells by inactivating the PI3K/AKT pathway [ 29 ]; and ginsenoside Rg3 can inhibit the mTOR signaling axis of SOX2, PI3K/Akt, and miR-429 to reduce the resistance to cisplatin [ 30 ].…”

Potential of the miR-200 Family as a Target for Developing Anti-Cancer Therapeutics

“…Since miR-200 family miRNAs are mostly decreased in anti-cancer drug-resistant cells compared to parental sensitive cells, it is necessary to develop therapeutic miR-200 family miRNA-mimics (miR-200-mimics) that can overcome the resistance to anti-cancer drugs. The overexpression of miR-200 family miRNAs has been reported to enhance chemosensitivity [ 107 , 108 , 111 ]. Drugs targeting miR-200 family-regulated genes can be combined with miR-200 family miRNA-mimics to overcome the resistance to anti-cancer drugs.…”

“…SOX2 is known to be a target of the miR-200 family in colorectal cancer [ 110 ]. miR-429 enhanced the sensitivity of gastric cancer cells to cisplatin by decreasing the expression of SOX2 and inhibiting PI3K/Akt/mammalian target of rapamycin (mTOR) signaling [ 111 ]. These reports further indicate the role of cancer stem cells in anti-cancer drug resistance.…”

Research progress of ginseng in the treatment of gastrointestinal cancers

“…Wang et al observed that β-elemene induces cell cycle arrest in the G2/M phase by regulating the ROS/AMPK/mTOR pathway ( Wang X et al, 2022 ).…”