Sulforaphane suppresses autophagy during the malignant progression of gastric carcinoma via activating miR-4521/PIK3R3 pathway

Abstract

Objective Sulforaphane, which exerts an effective anti-cancer ability, is a phytochemical converted from cruciferous plants. Here, we aimed to identify whether sulforaphane could suppress autophagy during the malignant progression of gastric carcinoma and to explore the underlying mechanisms. Methods SGC7901 cells were transfected with miR-4521 mimics, inhibitor, and pcDNA3.1- PIK3R3, and treated with sulforaphane or autophagy inhibitor. Cell proliferation, apoptosis, and miR-4521 or PIK3R3 expression were detected. Results MiR-4521 over-expression suppressed LC3-II/I ratio and Beclin-1 expression but induced p62 expression in SGC7901 cells. MiR-4521 also reduced gastric carcinoma cell proliferation and promoted apoptosis in vitro. In the mechanical observation, we identified that miR-4521 directly targeted PIK3R3 to repress its expression, and PIK3R3 up-regulation partly antagonized miR-4521-mediated autophagy, proliferation, and apoptosis in gastric carcinoma cells. In addition, sulforaphane exerted effective anti-cancer functions by repressing autophagy and growth in tumor cells at a concentration-dependent way. MiR-4521 inhibition or PIK3R3 over-expression weakened the anti-cancer functions of sulforaphane in gastric carcinoma cells. Conclusion Consequently, miR-4521 suppressed autophagy during the malignant progression of gastric carcinoma by targeting PIK3R3. Thus, miR-4521 may be applied as a therapeutic target for sulforaphane in gastric carcinoma.

Anticancer applications of phytochemicals in gastric cancer: Effects and molecular mechanism

“…Isorhamnetin induced GC cells autophagy via the PI3K pathway ( Li et al, 2021d ). Sulforaphane also suppressed cell autophagy during the progression of gastric cancer ( Mondal et al, 2016 ; Wang et al, 2021c ; Peng and Gu, 2021 ). Procyanidin exerted anti-cancer activity in GC by regulating autophagy ( Nie et al, 2016 ; Li et al, 2021c ).…”

An Overview of the Spices Used for the Prevention and Potential Treatment of Gastric Cancer

“…It has been shown that SFN can inhibit GC cell autophagy through the activation of the miR-4521/PIK3R3 (phosphoinositide-3-kinase regulatory subunit 3) pathway. The mediator miR-4521-dependent apoptosis in vitro was also observed [111]. Sulforaphane has been shown to have proliferation inhibitory, cell cycle arrest, and apoptosis induction abilities in GC cells.…”

Ferroptosis: Potential opportunities for natural products in cancer therapy

“…Subsequently, excessive free iron triggered ferroptosis in anaplastic thyroid cancer cells by inducing lipid peroxidation. Gastric carcinoma cells treated with sulforaphane exhibited increased levels of free iron, ROS, and MDA, as well as decreased levels of GSH and superoxide dismutase 2 (SOD2), indicating that this isothiocyanate triggers ferroptosis in cancer cells (Wen et al, 2023). Further studies have shown that sulforaphane activates PI3K and increases the expression of IRP2 and DMT1 in MGC‐803 cells, while PI3K inhibition eliminates the increase in IRP2 and DMT1 expression, indicating that sulforaphane inhibits the development of gastric carcinoma by regulating the PI3K/IRP2/DMT1 axis (Wen et al, 2023).…”

“…Gastric carcinoma cells treated with sulforaphane exhibited increased levels of free iron, ROS, and MDA, as well as decreased levels of GSH and superoxide dismutase 2 (SOD2), indicating that this isothiocyanate triggers ferroptosis in cancer cells (Wen et al, 2023). Further studies have shown that sulforaphane activates PI3K and increases the expression of IRP2 and DMT1 in MGC‐803 cells, while PI3K inhibition eliminates the increase in IRP2 and DMT1 expression, indicating that sulforaphane inhibits the development of gastric carcinoma by regulating the PI3K/IRP2/DMT1 axis (Wen et al, 2023). Furthermore, erianin extracted from Dendrobium chrysotoxum increased the N6‐methyladenosine modification of P53 and arachidonate 12‐lipoxygenase (ALOX12) mRNA by promoting methyltransferase‐like 3 (METTL3) expression, which enhanced ferroptosis in renal cancer stem cells by increasing the expression of these proteins (H. Shen et al, 2023).…”