• Biomolecules & Therapeutics
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• 제29권6호
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• pp.667-677
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• 2021

The elevated expression of the hyaluronan-mediated motility receptor (HMMR) is known to be highly associated with tumor progression in prostate cancer, but the molecular mechanisms underlying the regulation of HMMR expression remain unclear. Here, we report that mammalian target of rapamycin (mTOR) is a key regulator of HMMR expression, for which its kinase activity is required. Pharmacological inhibitors of mTOR, such as rapamycin and Torin2, markedly suppressed the mRNA level as well as the protein level of HMMR in LNCaP and PC-3 cells. Our data demonstrate that such regulation occurs at the transcription level. HMMR promoter reporter assays revealed that the transcription factor SRF is responsible for the mTOR-mediated transcriptional regulation of HMMR gene. Consistently, the suppression of HMMR expression by Torin2 was noticeably reversed by the overexpression of SRF. Moreover, our findings suggest that the SRF binding sites responsible for the transcriptional regulation of HMMR through the mTOR-SRF axis are located in HMMR promoter sequences carrying the first intron, downstream of the translational start site. Furthermore, the upregulation of HMMR by DHT was abolished by stimulation with rapamycin, prior to DHT treatment, suggesting that mTOR activity is required for the induction of HMMR expression by androgen. Collectively, our study provides new mechanistic insights into the role of mTOR/SRF/AR signaling in HMMR regulation in prostate cancer cells.

• Biomolecules & Therapeutics
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• 제28권2호
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• pp.184-194
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• 2020

Histone deacetylase (HDAC) inhibitors represent a novel class of anticancer agents, which can be used to inhibit cell proliferation and induce apoptosis in several types of cancer cells. In this study, we investigated the anticancer activity of MHY4381, a newly synthesized HDAC inhibitor, against human prostate cancer cell lines and compared its efficacy with that of suberoylanilide hydroxamic acid (SAHA), a well-known HDAC inhibitor. We assessed cell viability, apoptosis, cell cycle regulation, and other biological effects in the prostate cancer cells. We also evaluated a possible mechanism of MHY4381 on the apoptotic cell death pathway. The IC₅₀ value of MHY4381 was lower in DU145 cells (IC₅₀=0.31 µM) than in LNCaP (IC₅₀=0.85 µM) and PC-3 cells (IC₅₀=5.23 µM). In addition, the IC₅₀ values of MHY4381 measured in this assay were significantly lower than those of SAHA against prostate cancer cell lines. MHY4381 increased the levels of acetylated histones H3 and H4 and reduced the expression of HDAC proteins in the prostate cancer cell lines. MHY4381 increased G2/M phase arrest in DU145 cells, and G1 arrest in LNCaP cells. It also activated reactive oxygen species (ROS) generation, which induced apoptosis in the DU145 and LNCaP cells by increasing the ratio of Bax/Bcl-2 and releasing cytochrome c into the cytoplasm. Our results indicated that MHY4381 preferentially results in antitumor effects in DU145 and LNCaP cells via mitochondria-mediated apoptosis and ROS-facilitated cell death pathway, and therefore can be used as a promising prostate cancer therapeutic.

• Toxicological Research
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• 제22권1호
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• pp.31-37
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• 2006

It was previously found that melittin inhibited $NF-{\kappa}B$ activity by reacting with signal molecules of $NF-{\kappa}B$ which is critical contributor in cancer cell growth by induction of apoptotic cell death. We here investigated whether melittin inhibits cell growth of human prostate cancer cells through induction of apoptotic cell death, and the possible signal pathways. Melittin ($0{\sim}1\;{\mu}g/ml$) inhibited prostate cancer cell growth in a dose dependent manner. Conversely related to the growth inhibitory effect, melittin increased the induction of apoptotic cell death in a dose dependent manner. Melittin also inhibited DNA binding activity of $NF-{\kappa}B$, an anti-apoptotic transcriptional factor. Consistent with the induction of apoptotic cell death and inhibition of $NF-{\kappa}B$, melittin increased the expression of pro-apoptotic proteins caspase-3, and Bax but down-regulated anti-apoptotic protein Bcl-2. These findings suggest that melittin could inhibit prostate cancer cell growth, and this effect may be related with the induction of apoptotic cell death via inactivation of $NF-{\kappa}B$.

• Asian Pacific Journal of Cancer Prevention
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• 제16권16호
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• pp.6963-6966
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• 2015

Background: During the past few years, Hesa-A, a herbal-marine mixture, has been used to treat cancer as an alternative medicine in Iran. Based on a series of studies, it is speculated that Hesa-A possesses special cytotoxic effects on invasive tumors. To test this hypothesis, we investigated the selective anticancer effects of Hesa-A on several cancer cell lines with different metastatic potential. Materials and Methods: Hesa-A was prepared in normal saline as a stock solution of 10 mg/ml and further diluted to final concentrations of $100{\mu}/ml$, $200{\mu}g/ml$, $300{\mu}g/ml$ and $400{\mu}g/ml$. MTT-based cytotoxicity assays were performed with A549 (lung non small cancer), MCF-7 (breast adenocarcinoma), SKOV3 (ovarian cancer), and PC-3 (prostate adenocarcinoma) cells. Results: All treated cancer cells showed significant (P<0.01) or very significant (P<0.0001) differences in comparison to negative control at almost all of the tested doses ($100-400{\mu}g/ml$). At the lower dose ($100{\mu}g/ml$), Hesa-A reduced cell viability to 66%, 45.3%, 35.5%, 33.2% in SKOV3, A549, PC-3 and MCF-7 cells, respectively. Moreover, at the highest dose ($400{\mu}g/ml$), Hesa-A resulted in 88.5%, 86.6%, 84.9% and 79.3% growth inhibition in A549, MCF-7, PC-3 and SKOV3 cells, respectively. Conclusions: Hesa-A exert potent cytotoxic effects on different human cancer cells, especially those with a high metastatic potential.

• Asian Pacific Journal of Cancer Prevention
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• 제16권14호
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• pp.5703-5707
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• 2015

Background: Medicinal plants, especially examples rich in polyphenolic compounds, have been suggested to be chemopreventive on account of their antioxidative properties. Melissa officinalis L. (MO), an aromatic and medicinal plant, is well known in thios context. However, toxicity against cancer cells has not been fully studied. Here, we investigated the selective anticancer effects of an MO extract (MOE) in different human cancer cells. Materials and Methods: a hydro-alcoholic extract of MO was prepared and total phenolic content (TPC) and total flavonoid content (TFC) were determined by colorimetric assays. Antioxidant activity was determined by DPPH radical scavenging activity. MTT assays were used to evaluate cytotoxicity of different doses of MOE (0, 5, 20, 100, 250, 500, $1000{\mu}g/ml$) towards A549 (lung non small cell cancer cells), MCF-7 (breast adenocarcinoma), SKOV3 (ovarian cancer cells), and PC-3 (prostate adenocarcinoma) cells. Results: Significant (P<0.01) or very significant (P<0.0001) differences were observed in comparison to negative controls at all tested doses ($5-1000{\mu}g/ml$). In all cancer cells, MOE reduced the cell viability to values below 33%, even at the lowest doses. In all cases, $IC_{50}$ values were below $5{\mu}g/ml$. The mean growth inhibition was 73.1%, 86.7%, 79.9% and 77.8% in SKOV3, MCF-7 and PC-3 and A549 cells, respectively. Conclusions: Our results indicate that a hydro-alcoholic extract of MO possess a high potency to inhibit proliferation of different tumor cells in a dose independent manner, suggesting that an optimal biological dose is more important than a maximally tolerated one. Moreover, the antiprolifreative effect of MO seems to be tumor type specific, as hormone dependant cancers were more sensitive to antitumoral effects of MOE.

• 한국자원식물학회지
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• 제33권6호
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• pp.551-557
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• 2020

In this study, we were performed to elucidate the antioxidant and anticancer activity by leaves extracts from Acer tegmentosum (AT-L). In DPPH, ABTS radical scavenging activity, the AT-L revealed the high scavenging activity. Especially, the AT-L measured the highest ABTS radical scavenging activity, which is higher than ascorbic acid. The types of human cancer cells for evaluating the anticancer activity were colorectal cancer (SW480), prostate cancer (PC-3), breast cancer (MCF-7), pancreatic cancer (AsPC-1), lung cancer (A549) and liver cancer (HepG2). Human cancer cell viability was measured using MTT assay. Treatment of the AT-L decreased the cell viability and induced apoptosis in SW480 cells. These results suggest that extracts of the AT-L can be used as supplementary material for developing the natural antioxidant and anticancer drug for human cancer cells.

• 생명과학회지
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• 제22권11호
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• pp.1552-1557
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• 2012

Pipernonaline은 후추나무과에 속하는 필발(Piper longum Linn.)의 유도체로서 전립선 암세포에 대한 항암활성이 보고되고 있다. 하지만 실제 암세포 내에서 생물학적 정보를 가진 수 많은 유전자들에 대한 발현이 어떻게 이루어지고 있는지 알려진 바가 없다. 본 연구에 사용된 microarray 분석은 동시에 수 만개 이상의 유전자 발현양상을 한번에 관찰할 수 있는 기술로서 특정 질병의 유전학적 특성과 기전 연구를 더 광범위하게 연구 할 수 있는 기술이다. 본 연구에서는 전립선 암세포인 PC-3 세포에 pipernonaline을 처리하여 cDNA microarray를 실시하였다. 이후, DAVID database를 이용하여 gene ontology의 Biological Process를 분석하여 세포사멸과 세포주기, 세포성장 및 증식에 관련된 유전자들을 우선적으로 분석하였다. 그 결과, 세포주기관련 256개, 세포사멸관련 197개, 세포성장 및 증식관련에 154개의 유전자가 확인 되었다. 이러한 결과는 pipernonaline은 전립선 암세포 내에 존재하는 생물학적 신호전달체계에 관련된 유전자 발현을 조절함으로써 항암활성을 나타내 것을 알 수 있었고, 이후 이러한 microarray의 추가적인 분석은 암세포 내 새로운 유전자의 탐색 및 메커니즘을 규명하는데 유용하게 사용할 수 있을 것으로 사료된다.

• Biomolecules & Therapeutics
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• 제22권5호
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• pp.475-475
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• 2014

• 동의생리병리학회지
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• 제26권4호
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• pp.437-440
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• 2012

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that regulates various cellular processes such as cell survival, angiogenesis and proliferation. In the present study, we examined that Cryptotanshione(CT), a tanshinone from oriental traditional medicinal herb Danshen (Salvia miltiorrhiza Bunge), had the inhibitory effects on hypoxia-mediated activation of STAT3 in androgen independent human prostate cancer PC-3 cells. CT inhibited the protein expression of hypoxia-inducible factor-1alpha (HIF-$1{\alpha}$) under hypoxic condition. Consistently, CT blocked hypoxia-induced phosphorylation and nuclear accumulation of STAT3. In addition, CT reduced cellular of vascular endothelial growth factor (VEGF), a critical angiogenic factor and a target gene of STAT3 induced under hypoxia. Of note, chromatin immunoprecipitation (ChiP) assay revealed that CT inhibited binding of STAT3 to VEGF promoter. Taken together, our results suggest that CT has anti-angiogenic activity by disturbing the binding STAT3 to the VEGF promoter in PC-3 cells.

• BMB Reports
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• 제31권5호
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• pp.508-514
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• 1998

We studied the effects of ASC-17D rat Sertoli cell-conditioned media (rSCCM) on the proliferation of the DU145 prostate cancer cells. rSCCM was prepared from ASC-17D cells cultured in DMEM/F-12 serum-free media at a nonpermissive temperature of $40^{\circ}C$, which is the condition for the high expression of c1usterin. We found that rSCCM could inhibit the proliferation of DU145 cells by arresting the cell cycle in the G1 phase in a dose-dependent manner. This growth arresting activity was abolished by boiling rSCCM for 5 min. The G1 growth-inhibiting activity of rSCCM was also detected in other prostate-originated cancer cells examined (i.e., LNCaP and PC-3) but not in other cells (ASC-17D, HepG2, SK-N-SH, and NIH3T3). Western blot analysis of partially purified growth inhibiting fractions with the clusterin antibody showed that the cytostatic factor in rSCCM was not c1usterin. This cytostatic factor was semi purified by DEAE-Sepharose, ammonium sulfate precipitation, and Phenyl-Sepharose column chromatography, and was estimated to have a molecular weight of 88 kDa by Sephacryl S-300 gel filtration.