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. 2020 Mar 27;40(3):BSR20192826.
doi: 10.1042/BSR20192826.

Isorhamnetin inhibited the proliferation and metastasis of androgen-independent prostate cancer cells by targeting the mitochondrion-dependent intrinsic apoptotic and PI3K/Akt/mTOR pathway

Fangzhen Cai  1 , Yanmei Zhang  1 , Jianwei Li  1 , Sihuai Huang  1 , Ruilin Gao  1
Affiliations

Isorhamnetin inhibited the proliferation and metastasis of androgen-independent prostate cancer cells by targeting the mitochondrion-dependent intrinsic apoptotic and PI3K/Akt/mTOR pathway

Fangzhen Cai et al. Biosci Rep. .

Abstract

The present study investigated the effects of Isorhamnetin on two types of prostate cancer cells (androgen-independent and androgen-dependent) and explored its possible mechanisms underlying such effects. Treatment with Isorhamnetin significantly inhibited cell growth and induced lactate dehydrogenase (LDH) release of androgen-independent DU145 and PC3 prostate cancer cells, but exhibited almost no toxicity effect on androgen-dependent LNCaP prostate cancer cell line or normal human prostate epithelial PrEC cells, which was achieved by the induction of apoptosis in a mitochondrion-dependent intrinsic apoptotic pathway. Furthermore, Isorhamnetin inhibited cell migration and invasion in concentration-dependent manners by enhancing mesenchymal-epithelial transition (MET) and inhibiting matrix metalloproteinase (MMP) 2 (MMP-2) and MMP-9 overexpression. In addition, Isorhamnetin also down-regulated the expression of phosphorylated PI3K (p-P13K), Akt (p-Akt), and mTOR (p-mTOR) proteins in both cancer cells, revealing Isorhamnetin to be a selective PI3K-Akt-mTOR pathway inhibitor. In summary, these findings propose that Isorhamnetin might be a novel therapeutic candidate for the treatment of androgen-independent prostate cancer.

Keywords: Apoptosis; Isorhamnetin; Metastasis; PI3K/Akt/mTOR; Prostate cancer.

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Conflict of interest statement

The authors declare that there are no competing interests associated with the manuscript.

Figures

Figure 1
Figure 1. Chemical structure of isorhamnetin
Figure 2
Figure 2. Isorhamnetin inhibits cell growth and induces LDH release in prostate cancer cell lines
(A) Effects of Isorhamnetin (2.5, 5, 10, and 20 μM) on the cell growth of DU145 cells. (B) Effects of Isorhamnetin (2.5, 5, 10, and 20 μM) on the cell growth of PC3 cells. (C) Effects of Isorhamnetin (2.5, 5, 10, and 20 μM) on the cell growth of LNCaP cells. (D) Effects of Isorhamnetin (2.5, 5, 10, and 20 μM) on the cell growth of PrEC cells. (E) Effects of Isorhamnetin (5, 10, and 20 μM) on the LDH release of DU145 and PC3 cells. (F) Effects of Isorhamnetin (5, 10, and 20 μM) on the LDH release of LNCaP and PrEC cells. Related data appear as the means ± SD of three separate assays. *P<0.05 and **P<0.01 vs control.
Figure 3
Figure 3. Isorhamnetin induces apoptotic cell death in prostate cancer cell lines
(A) Effects of Isorhamnetin (5, 10, and 20 μM) on the apoptotic cell death of DU145 cells. (B) Effects of Isorhamnetin (5, 10, and 20 μM) on the apoptotic cell death of DU145 cells. Related data appear as the means ± SD of three separate assays. *P<0.05 and **P<0.01 vs control.
Figure 4
Figure 4. Isorhamnetin alters the expression of apoptosis-related protein in prostate cancer cell lines
(A) Effects of Isorhamnetin (5, 10, and 20 μM) on the expression of Bax, Bcl-2, and cytoplasmic cytochrome-c protein in DU145 cells. (B) Relative levels of each protein (Bax, Bcl-2, and cytoplasmic cytochrome-c) compared with control (%) in DU145 cells. (C) Effects of Isorhamnetin (5, 10, and 20 μM) on the expression of cleaved-caspase 9, cleaved-caspase 3, and cleaved-PARP protein in PC3 cells. (D) Relative levels of each protein (cleaved-caspase 9, cleaved-caspase 3, and cleaved-PARP) compared with control (%) in PC3 cells. Related data appear as the means ± SD of three separate assays. *P<0.05, **P<0.01, and ***P<0.001 vs control.
Figure 5
Figure 5. Isorhamnetin inhibits invasion and migration in prostate cancer cell lines
(A) Effects of Isorhamnetin (5, 10, and 20 μM) on the invasion of DU145 cells. (B) Effects of Isorhamnetin (5, 10, and 20 μM) on the migration of DU145 cells. (C) Effects of Isorhamnetin (5, 10, and 20 μM) on the invasion of PC3 cells. (D) Effects of Isorhamnetin (5, 10, and 20 μM) on the migration of PC3 cells. Related data appear as the means ± SD of three separate assays. *P<0.05, **P<0.01, and ***P<0.001 vs control.
Figure 6
Figure 6. Isorhamnetin alters the expression of EMT-related protein in prostate cancer cell lines.
(A) Effects of Isorhamnetin (5, 10, and 20 μM) on the expression of E-cadherin, Vimentin, N-cadherin, MMP-2, and MMP-9 protein in DU145 cells. (B) Relative levels of each protein (E-cadherin, Vimentin, N-cadherin, MMP-2, and MMP-9) compared with control (%) in DU145 cells. (C) Effects of Isorhamnetin (5, 10, and 20 μM) on the expression of E-cadherin, Vimentin, N-cadherin, MMP-2, and MMP-9 protein in PC3 cells. (D) Relative levels of each protein (E-cadherin, Vimentin, N-cadherin, MMP-2, and MMP-9) compared with control (%) in PC3 cells. Related data appear as the means ± SD of three separate assays. *P<0.05, **P<0.01, and ***P<0.001 vs control.
Figure 7
Figure 7. Isorhamnetin inhibits the phosphorylation expression of PI3K, Akt and mTOR protein in prostate cancer cell lines
(A) Effects of Isorhamnetin (5, 10, and 20 μM) on the expression of p-PI3K, PI3K, p-Akt, Akt, p-mTOR, and mTOR protein in DU145 cells. (B) Relative levels of each protein (p-PI3K, PI3K, p-Akt, Akt, p-mTOR, and mTOR) compared with control (%) in DU145 cells. (C) Effects of Isorhamnetin (5, 10, and 20 μM) on the expression of p-PI3K, PI3K, p-Akt, Akt, p-mTOR, and mTOR protein in PC3 cells. (D) Relative levels of each protein (p-PI3K, PI3K, p-Akt, Akt, p-mTOR, and mTOR) compared with control (%) in PC3 cells. Related data appear as the means ± SD of three separate assays. *P<0.05, **P<0.01, and ***P<0.001 vs control.
Figure 8
Figure 8. PI3K/Akt/mTOR pathway inhibitor (LY294002/deguelin/rapamycin) or Isorhamnetin (20 μM) treatment inhibits the phosphorylation expression of PI3K, Akt and mTOR protein, induces apoptotic cell death and inhibits invasion and migration in prostate cancer cell lines
(A) Effects of Isorhamnetin (20 μM) or LY294002/deguelin/rapamycin on the expression of p-PI3K, PI3K, p-Akt, Akt, p-mTOR, and mTOR protein in DU145 cells. (B) Effects of Isorhamnetin (20 μM) or LY294002/deguelin/rapamycin on the expression of p-PI3K, PI3K, p-Akt, Akt, p-mTOR, and mTOR protein in PC3 cells. (C) Effects of Isorhamnetin (20 μM) or LY294002/deguelin/rapamycin on the apoptotic cell death, invasion, and migration of DU145 cells. (D) Effects of Isorhamnetin (20 μM) or LY294002/deguelin/rapamycin on the apoptotic cell death, invasion, and migration of DU145 cells. Related data appear as the means ± SD of three separate assays. *P<0.05, **P<0.01, and ***P<0.001 vs control.
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