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. 2021 Jun 9:12:681338.
doi: 10.3389/fphar.2021.681338. eCollection 2021.

Levobupivacaine Induces Ferroptosis by miR-489-3p/SLC7A11 Signaling in Gastric Cancer

Shun-Hong Mao  1 , Chun-Hua Zhu  1 , Yu Nie  1 , Jian Yu  1 , Lei Wang  1
Affiliations

Levobupivacaine Induces Ferroptosis by miR-489-3p/SLC7A11 Signaling in Gastric Cancer

Shun-Hong Mao et al. Front Pharmacol. .

Abstract

Gastric cancer is one of the most the prevalent malignancies and the therapeutic strategies for patients with gastric cancer remains limited. Local anesthetic levobupivacaine has demonstrated potential anti-cancer property, but its correlation with gastric cancer and ferroptosis is poor understood. Here, we identified the novel function of levobupivacaine in regulating ferroptosis of gastric cancer cells. The treatment of levobupivacaine suppressed gastric cancer cell viabilities and Edu-positive cell proportions. The gastric cancer cell growth was reduced by levobupivacaine in vivo. Moreover, the treatment of levobupivacaine enhanced erastin-induced inhibitory impact on gastric cancer cell viabilities. The levels of Fe2+/iron and lipid ROS were induced by levobupivacaine in erastin and RSL3-stimulated gastric cancer cells. levobupivacaine-upregulated miR-489-3p enhanced ferroptosis of gastric cancer cells by targeting SLC7A11 VSports手机版. MiR-489-3p was involved in levobupivacaine-induced ferroptosis of gastric cancer cells. Levobupivacaine/miR-489-3p/SLC7A11 axis attenuates gastric cancer cell proliferation in vitro. Therefore, we concluded that the local anesthetic levobupivacaine induced ferroptosis of gastric cancer cells to repress gastric cancer cell growth by miR-489-3p/SLC7A11 axis. .

Keywords: SLC7A11; ferroptosis; gastric cancer; levobupivacaine; mir-489-3p. V体育安卓版.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Levobupivacaine represses survival of gastric cancer cells in vitro. (A) The GES-1, HGC27, and SGC7901 cells were treated with levobupivacaine at the indicated concentrations. MTT assays for cell viability analysis. (B–E) HGC27 and SGC7901 cells were treated with saline or levobupivacaine (2 mM). (B) MTT assays for cell viability analysis. (C,D) Edu assays for cell proliferation analysis. (E,F) Flow cytometry analysis of apoptosis. The experiments were performed independently three times (mean ± SD, **p < 0.01).
FIGURE 2
FIGURE 2
Levobupivacaine represses survival of gastric cancer cells in vivo. (A–E) The mice were injected with SGC7901 cells and treated with levobupivacaine (40 μmol/kg). The tumor tissues (A), tumor volume (B), and tumor weight. (C) were shown. N = 5, mean ± SD, **p < 0.01.
FIGURE 3
FIGURE 3
Levobupivacaine enhances ferroptosis of gastric cancer cells. (A,B) HGC27 and SGC7901 cells were co-treated with erastin (5 μM) and levobupivacaine (2 mM). MTT assays for cell viability analysis. (C–H) The erastin (5 μM) and RSL3 (1 μM)-stimulated HGC27 and SGC7901 cells were treated with saline or levobupivacaine (2 mM). The Fe2+ (C,D), iron. (E,F), and ROS levels (G,H) were analyzed. The experiments were performed independently three times (mean ± SD, **p < 0.01).
FIGURE 4
FIGURE 4
Levobupivacaine-upregulated miR-489-3p enhances ferroptosis of gastric cancer cells. (A) HGC27 and SGC7901 cells were treated with saline or levobupivacaine (2 mM). The qPCR analysis of miR-489-3p expression. (B,C) HGC27 and SGC7901 cells were co-treated with erastin (5 μM) and miR-489-3p mimic. MTT assays for cell viability analysis. (D–I) The erastin (5 μM) and RSL3 (1 μM)-stimulated HGC27 and SGC7901 cells were treated with miR-489-3p mimic. The Fe2+ (D,E), iron (F,G), and ROS levels (H,I) were analyzed. The experiments were performed independently three times (mean ± SD, **p < 0.01).
FIGURE 5
FIGURE 5
MiR-489-3p is involved in levobupivacaine-induced ferroptosis of gastric cancer cells. (A–H) The erastin (5 μM)-treated HGC27 and SGC7901 cells were co-treated with levobupivacaine and miR-489-3p inhibitor. (A,B) MTT assays for cell viability analysis. The Fe2+ (C,D), iron (E,F), and ROS levels (G,H) were analyzed. The experiments were performed independently three times (mean ± SD, **p < 0.01).
FIGURE 6
FIGURE 6
MiR-489-3p targets ferroptosis inhibitor SLC7A11 in gastric cancer cells. (A) The binding prediction between SLC7A11 and miR-489-3p in ENCORI database. (B,C) HGC27 and SGC7901 cells were treated with miR-489-3p mimic. The luciferase activity of SLC7A11 mRNA 3′UTR (B) and SLC7A11 mRNA expression (D) were detected (D) HGC27 and SGC7901 cells were co-treated with levobupivacaine and miR-489-3p inhibitor. Western blot analysis of SLC7A11 expression. The experiments were performed independently three times (mean ± SD, **p < 0.01, ***p < 0.001).
FIGURE 7
FIGURE 7
SLC7A11 is involved in miR-489-3p-induced ferroptosis of gastric cancer cells. (A–H) The erastin (5 μM)-treated HGC27 and SGC7901 cells were co-treated with miR-489-3p mimic and SLC7A11 overexpression vectors. (A,B) MTT assays for cell viability analysis. The Fe2+ (C,D), iron (E,F), and ROS levels (G,H) were analyzed (I). The erastin (5 μM)-treated HGC27 and SGC7901 cells co-treated with miR-489-3p inhibitor and SLC7A11 siRNA. The cell viability was detected by MTT assays. The experiments were performed independently three times (mean ± SD, **p < 0.01).
FIGURE 8
FIGURE 8
Levobupivacaine/miR-489-3p/SLC7A11 axis attenuates gastric cancer cell proliferation in vitro. (A–D) HGC27 and SGC7901 cells were co-treated with levobupivacaine and SLC7A11 overexpression vectors or miR-489-3p inhibitor. (A,B) MTT assays for cell viability analysis. (C,D) Flow cytometry analysis of apoptosis. (E–J) HGC27 and SGC7901 cells were co-treated with levobupivacaine and miR-489-3p inhibitor or co-treated with levobupivacaine, miR-489-3p inhibitor, and SLC7A11 siRNA. The Fe2+ (E,F), iron (G,H), and ROS levels (I,J) were analyzed. The experiments were performed independently three times (mean ± SD, **p < 0.01).
FIGURE 9
FIGURE 9
Levobupivacaine enhances inhibitory effect of erastin on gastric cancer cell growth in vivo. The mice were injected with SGC7901 cells and treated with erastin (15 mg/kg) and levobupivacaine (40 μmol/kg). The tumor tissues (A) and tumor weight (B) were shown. (C) The lipid ROS, Fe2+, iron levels were analyzed. N = 5, mean ± SD, **p < 0.01.
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