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. 2024 Apr 15;14(4):1935-1946.
doi: 10.62347/PMYV3832. eCollection 2024.

Verteporfin suppressed mitophagy via PINK1/parkin pathway in endometrial cancer

Affiliations

Verteporfin suppressed mitophagy via PINK1/parkin pathway in endometrial cancer

Ming-Ming Zhao et al. Am J Cancer Res. .

Abstract

Endometrial cancer (EC) is a malignancy that poses a threat to woman's health worldwide. Building upon prior work, we explored the inhibitory effect of verteporfin on EC. We showed that verteporfin can damage the mitochondria of EC cells, leading to a decrease of mitochondrial membrane potential and an increase in ROS (reactive oxygen species). In addition, verteporfin treatment was shown to inhibit the proliferation and migration of EC cells, promote apoptosis, and reduce the expression of mitophagy-related proteins PINK1/parkin and TOM20. The ROS inhibitor N-Acetyl Cysteine was able to rescue the expression of PINK1/parkin proteins. This suggests that verteporfin may inhibit mitophagy by elevating ROS levels, thereby inhibiting EC cell viability. The effect of verteporfin on mitophagy supports further investigation as a potential therapeutic option for EC.

Keywords: Endometrial cancer; PINK1/parkin pathway; mitophagy; verteporfin.

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Conflict of interest statement

None.

Figures

Figure 1
Figure 1
Endometrial cancer patients with high expression of mitophagy-related genes have a superior prognosis. Survival time was longer in EC patients with high PINK1 (A), TOM20 (B), LC3BI (C), and LC3BII (D) gene expression.
Figure 2
Figure 2
The effect of verteporfin on the proliferation, migration and apoptosis of EC cells. Concentration-dependent effect of verteporfin on cell viability was analyzed with the CCK-8 assay in Hec1A (A) and Ishikawa (B) cell lines. A scratch assay showed that 1 μM or 3 μM of verteporfin treatment for 12 h significantly inhibited cell migration in Hec1A (C) and Ishikawa (E) cells, and there was a statistically significant difference between the migration rates of the control group and the verteporfin-treated group (D, F). A flow cytometry assay for apoptosis showed that the percentage of apoptosis was elevated in Hec1A (G) cell line after 1-4 μM verteporfin treatment for 24 h. There was a statistically significant difference between the control and verteporfin-treated groups for the Hec1A cell line. Data are presented as means ± SD from three independent experiments. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 compared with the control group.
Figure 3
Figure 3
Verteporfin disrupts mitochondrial morphology and inhibits mitochondrial viability. Mitochondrial ultrastructure (A, B) and immunofluorescence (C, E) of DAPI and MitoTracker were evaluated after treatment with 1 μM or 3 μM verteporfin in Hec1A and Ishikawa cell lines. The difference in mean fluorescence intensity (D, F) between the control and verteporfin-treated groups was statistically significant. Data are presented as means ± SD from three independent experiments. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 compared with control group.
Figure 4
Figure 4
Verteporfin decreases mitochondrial membrane potential and increases ROS levels in EC cells. A-D. JC-1 staining is depicted. The ratio of red/green fluorescence reflects changes in the mitochondrial membrane potential. Scale bar: 100 μm. E-G. Measurement of ROS by DCFH-DA after treatment with verteporfin. Scale bar: 100 μm. Data are presented as means ± SD from three independent experiments. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 compared with the control group.
Figure 5
Figure 5
Verteporfin reduces the expression level of the mitophagy-related protein PINK1/parkin in endometrial cells. Cells were treated with verteporfin (1 μM or 3 μM) alone or verteporfin plus NAC (2 mM) for 24 h. Representative western blot images of PINK/parkin in Hec1A (A) and Ishikawa (B) cell lines are shown. Quantitative analysis of YAP/GAPDH, PINK1/GAPDH and parkin/GAPDH in the Hec1A cell line (C), YAP/GAPDH, PINK1/GAPDH and parkin/GAPDH in the Ishikawa cell line (D) are presented. Data are shown as means ± SD from three independent experiments. *P<0.05, **P<0.01, compared with the control group. Western blot image of PINK1/parkin and TOM20 treated by verteporfin and the ROS inhibitor NAC in Hec1A (E) and Ishikawa (F) cell lines.

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