Inhibition of STAT3/PD-L1 and Activation of miR193a-5p Are Critically Involved in Apoptotic Effect of Compound K in Prostate Cancer Cells

Since the signal transducer and activator of transcription 3 (STAT3)/programmed death-ligand 1 (PD-L1) signaling plays an important role in tumor-immune microenvironments, in the present study, the role of STAT3/PD-L1 signaling in the apoptotic mechanism of an active ginseng saponin metabolite compound K (CK) was investigated in human prostate cancer cells. Here, CK exerted significant cytotoxicity without hurting RWPE1 normal prostate epithelial cells, increased sub-G1 and cleavage of Poly ADP-ribose polymerase (PARP) and attenuated the expression of pro-PARP and Pro-cysteine aspartyl-specific protease3 (pro-caspase-3) in LANCap, PC-3 and DU145 cells. Further, CK attenuated the expression of p-STAT3 and PD-L1 in DU145 cells along with disrupted the binding of STAT3 to PD-L1. Furthermore, CK effectively abrogated the expression of p-STAT3 and PD-L1 in interferon-gamma (INF-γ)-stimulated DU145cells. Additionally, CK suppressed the expression of vascular endothelial growth factor (VEGF), transforming growth factor-β (TGF-β), interleukin 6 (IL-6) and interleukin 10 (IL-10) as immune escape-related genes in DU145 cells. Likewise, as STAT3 targets genes, the expression of CyclinD1, c-Myc and B-cell lymphoma-extra-large (Bcl-xL) was attenuated in CK-treated DU145 cells. Notably, CK upregulated the expression of microRNA193a-5p (miR193a-5p) in DU145 cells. Consistently, miR193a-5p mimic suppressed p-STAT3, PD-L1 and pro-PARP, while miR193a-5p inhibitor reversed the ability of CK to attenuate the expression of p-STAT3, PD-L1 and pro-PARP in DU145 cells. Taken together, these findings support evidence that CK induces apoptosis via the activation of miR193a-5p and inhibition of PD-L1 and STAT3 signaling in prostate cancer cells.

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Cytostatic Action of Novel Histone Deacetylase Inhibitors in Androgen Receptor-Null Prostate Cancer Cells

Pharmaceuticals ◽

10.3390/ph14020103 ◽

2021 ◽

Vol 14 (2) ◽

pp. 103

Author(s):

Zohaib Rana ◽

Joel D. A. Tyndall ◽

Muhammad Hanif ◽

Christian G. Hartinger ◽

Rhonda J. Rosengren

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Cancer Cells ◽

Hdac Inhibitors ◽

G1 Arrest ◽

Prostate Cancer Cells ◽

Prostate Tumors ◽

Normal Prostate ◽

Pc3 Cells ◽

Du145 Cells

Androgen receptor (AR)-null prostate tumors have been observed in 11–24% of patients. Histone deacetylases (HDACs) are overexpressed in prostate tumors. Therefore, HDAC inhibitors (Jazz90 and Jazz167) were examined in AR-null prostate cancer cell lines (PC3 and DU145). Both Jazz90 and Jazz167 inhibited the growth of PC3 and DU145 cells. Jazz90 and Jazz167 were more active in PC3 cells and DU145 cells in comparison to normal prostate cells (PNT1A) and showed a 2.45- and 1.30-fold selectivity and higher cytotoxicity toward DU145 cells, respectively. Jazz90 and Jazz167 reduced HDAC activity by ~60% at 50 nM in PC3 lysates. At 4 μM, Jazz90 and Jazz167 increased acetylation in PC3 cells by 6- to 8-fold. Flow cytometry studies on the cell phase distribution demonstrated that Jazz90 causes a G0/G1 arrest in AR-null cells, whereas Jazz167 leads to a G0/G1 arrest in DU145 cells. However, apoptosis only occurred at a maximum of 7% of the total cell population following compound treatments in PC3 and DU145 cells. There was a reduction in cyclin D1 and no significant changes in bcl-2 in DU145 and PC3 cells. Overall, the results showed that Jazz90 and Jazz167 function as cytostatic HDAC inhibitors in AR-null prostate cancer cells.

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Differential effects of transforming growth factor β on human prostate cancer cells in vitro

Molecular and Cellular Endocrinology ◽

10.1016/0303-7207(89)90115-9 ◽

1989 ◽

Vol 62 (1) ◽

pp. 79-87 ◽

Cited By ~ 111

Author(s):

George Wilding ◽

Gerhard Zugmeier ◽

Cornelius Knabbe ◽

Katherine Flanders ◽

Edward Gelmann

Keyword(s):

Prostate Cancer ◽

Growth Factor ◽

Cancer Cells ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Human Prostate ◽

Human Prostate Cancer ◽

Prostate Cancer Cells ◽

Differential Effects

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Maslinic acid inhibits the metastatic capacity of DU145 human prostate cancer cells: possible mediation via hypoxia-inducible factor-1α signalling

British Journal Of Nutrition ◽

10.1017/s0007114512000967 ◽

2012 ◽

Vol 109 (2) ◽

pp. 210-222 ◽

Cited By ~ 24

Author(s):

So Young Park ◽

Chu Won Nho ◽

Dae Young Kwon ◽

Young-Hee Kang ◽

Ki Won Lee ◽

...

Keyword(s):

Prostate Cancer ◽

Growth Factor ◽

Cancer Cells ◽

Kinase Inhibitor ◽

Hypoxia Inducible Factor ◽

Human Prostate Cancer ◽

Prostate Cancer Cells ◽

Maslinic Acid ◽

Metastatic Capacity ◽

Du145 Cells

Maslinic acid is found in various natural sources, most notably in pomace olive oil, and exerts pro-apoptotic activities in various cancer cells in vitro. In the present study, DU145 human prostate cancer cells were cultured with 0–25 μm-maslinic acid to examine the effects of maslinic acid on the metastatic capacity of prostate cancer cells. Maslinic acid significantly (P <0·05) inhibited the basal and epidermal growth factor (EGF)-induced migration (27–64 %), invasion (23–60 %) and adhesion (8–40 %) of DU145 cells. Maslinic acid significantly (P <0·05) down-regulated both basal and EGF-stimulated secretion of matrix metalloproteinase (MMP)-9 (25–67 %), MMP-2 (50–86 %), urokinase-type plasminogen activator (uPA, about 100 %), vascular endothelial growth factor (VEGF, 98–100 %) and tissue inhibitors of metalloproteinases (TIMP)-1, as well as expression of uPA receptor (uPAR), intercellular adhesion molecules (22–33 %), vascular cell adhesion molecules (23–46 %) and E-cadherin, whereas it increased TIMP-2 secretion. Maslinic acid dramatically reduced the levels of hypoxia-inducible factor-1α (HIF-1α) protein and mRNA; the reduction was accompanied by reduced stability, nuclear levels and transcriptional activity of HIF-1α. The levels of phospho-Akt and phospho-extracellular signal-related kinase (ERK) were reduced in cells treated with maslinic acid, and the phosphoinositide 3-kinase inhibitor LY294002 and the mitogen-activated protein kinase kinase inhibitor PD98059 reduced HIF-1α levels and VEGF secretion. The results show that maslinic acid markedly inhibited the migration, invasion and adhesion of DU145 prostate cancer cells. Suppressing HIF-1α activation by inhibiting Akt and ERK activation may be part of the mechanism by which maslinic acid inhibited uPAR, E-cadherin, VEGF and MMP expression in DU145 cells.

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