Targeting Mitochondrial Metabolism in Prostate Cancer with Triterpenoids

Metabolic reprogramming is a hallmark of malignancy. It implements profound metabolic changes to sustain cancer cell survival and proliferation. Although the Warburg effect is a common feature of metabolic reprogramming, recent studies have revealed that tumor cells also depend on mitochondrial metabolism. Due to the essential role of mitochondria in metabolism and cell survival, targeting mitochondria in cancer cells is an attractive therapeutic strategy. However, the metabolic flexibility of cancer cells may enable the upregulation of compensatory pathways, such as glycolysis, to support cancer cell survival when mitochondrial metabolism is inhibited. Thus, compounds capable of targeting both mitochondrial metabolism and glycolysis may help overcome such resistance mechanisms. Normal prostate epithelial cells have a distinct metabolism as they use glucose to sustain physiological citrate secretion. During the transformation process, prostate cancer cells consume citrate to mainly power oxidative phosphorylation and fuel lipogenesis. A growing number of studies have assessed the impact of triterpenoids on prostate cancer metabolism, underlining their ability to hit different metabolic targets. In this review, we critically assess the metabolic transformations occurring in prostate cancer cells. We will then address the opportunities and challenges in using triterpenoids as modulators of prostate cancer cell metabolism.

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Cisplatin and Paclitaxel Modulated the Cell Survival Potential of Prostate Cancer Cells

Proceedings ◽

10.3390/proceedings2019040042 ◽

2020 ◽

Vol 40 (1) ◽

pp. 42

Author(s):

Kashani ◽

Kilbas ◽

Yerlikaya ◽

Gurkan ◽

Arisan

Keyword(s):

Prostate Cancer ◽

Cell Viability ◽

Cell Survival ◽

Cancer Cells ◽

Cancer Cell ◽

Prostate Cancer Cell ◽

Dependent Manner ◽

Prostate Cancer Cells ◽

Cell Viability Assay ◽

Chemotherapy Drugs

Prostate cancer is the second common cause of death among men worldwide. In the treatment of prostate cancer, conventional chemotherapeutics are commonly used. The plant alkaloid Paclitaxel and platinum-based cisplatin are the most common chemotherapy drugs. The transcription factor p53 has a potential target in the regulation of cell response to DNA damage of prostate cancer. Although the effectiveness of these drugs on prostate cancer cell progression had been proved, the mechanistic action of these drugs on the progression of the disease is not detailed explained. In this study, we aim to examine the function of p53 overexpression in prostate cancer cell survival. Therefore, we treated wild type (wt) and p53 overexpressed PC3 (p53+) prostate cancer cells with cisplatin or paclitaxel. According to the MTT Cell Viability assay, cisplatin (12.5–25–50 µM) was found to be more effective decreasing PC3 and PC3 p53+ cell viability in a dose-dependent manner compared to paclitaxel (12.5–25–50 nM). Colony formation assay showed that treatment of cells with cisplatin or paclitaxel caused the loss of colony forming ability of PC3 and PC3 p53+ cells. In addition, the critical apoptotic markers Caspase-3 and Caspase-9 expressions were altered with cisplatin or paclitaxel treated PC3 wt and p53+ cells.

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SOX30, a target gene of miR-653-5p, represses the proliferation and invasion of prostate cancer cells through inhibition of Wnt/β-catenin signaling

Cellular & Molecular Biology Letters ◽

10.1186/s11658-019-0195-4 ◽

2019 ◽

Vol 24 (1) ◽

Cited By ~ 4

Author(s):

Qiang Fu ◽

Zhenye Sun ◽

Fan Yang ◽

Tianci Mao ◽

Yanyao Gao ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Cancer Cell ◽

Target Gene ◽

Prostate Cancer Cell ◽

Luciferase Reporter ◽

Prostate Cancer Cells ◽

Normal Prostate ◽

Proliferation And Invasion ◽

In Cells

Abstract Background Sex-determining region Y-box containing gene 30 (SOX30) is a newly identified tumor-associated gene in several types of cancer. However, whether SOX30 is involved in the development and progression of prostate cancer remains unknown. This study investigated the potential role of SOX30 in prostate cancer. Methods Prostate cancer cell lines and a normal prostate epithelial cell line were used for the experiments. The expression of SOX30 was determined using quantitative real-time PCR and western blot analysis. The malignant cellular behaviors of prostate cancer were assessed using the Cell Counting Kit-8, colony formation and Matrigel invasion assays. The miRNA–mRNA interaction was validated using the dual-luciferase reporter assay. Results SOX30 expression was lower in cells of prostate cancer lines than in cells of the normal prostate epithelial line. Its overexpression repressed the proliferation and invasion of prostate cancer cells. SOX30 was identified as a target gene of microRNA-653-5p (miR-653-5p), which is upregulated in prostate cancer tissues. MiR-653-5p overexpression decreased SOX30 expression, while its inhibition increased SOX30 expression in prostate cancer cells. MiR-653-5p inhibition also markedly restricted prostate cancer cell proliferation and invasion. SOX30 overexpression or miR-653-5p inhibition significantly reduced β-catenin expression and downregulated the activation of Wnt/β-catenin signaling. SOX30 knockdown significantly reversed the miR-653-5p inhibition-mediated inhibitory effect on the proliferation, invasion and Wnt/β-catenin signaling in prostate cancer cells. Conclusions These results reveal a tumor suppressive function for SOX30 in prostate cancer and confirmed the gene as a target of miR-653-5p. SOX30 upregulation due to miR-653-5p inhibition restricted the proliferation and invasion of prostate cancer cells, and this was associated with Wnt/β-catenin signaling suppression. These findings highlight the importance of the miR-653-5p–SOX30–Wnt/β-catenin signaling axis in prostate cancer progression.

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LSD1 Promotes Prostate Cancer Cell Survival by Destabilizing FBXW7 at Post-Translational Level

Frontiers in Oncology ◽

10.3389/fonc.2020.616185 ◽

2021 ◽

Vol 10 ◽

Author(s):

Xu-ke Qin ◽

Yang Du ◽

Xiu-heng Liu ◽

Lei Wang

Keyword(s):

Prostate Cancer ◽

Cell Survival ◽

Cell Lines ◽

Cancer Cell ◽

Mrna Level ◽

Knock Down ◽

Catalytic Inhibitor ◽

Cancer Cell Survival ◽

Demethylase Activity ◽

The Impact

Prostate cancer (PCa) is the most common cancer in men and the fifth leading cause of cancer death worldwide. Unfortunately, castration-resistant prostate cancer (CRPCa) is incurable with surgical treat and prone to drug resistance. Therefore, it is of great importance to find a new target for treatment. LSD1 is up-regulated in PCa and related with prognosis. The high-expression LSD1 has been shown to be a potential target for treatment and is widely studied for its demethylase-activity. However, its demethylation-independent function remains to be elusive in PCa. Recent study shows that LSD1 can destabilize cancer suppressor protein FBXW7 without demethylation-function. Hence, we hope to investigate the impact of non-canonical function of LSD1 on PCa cell survival. We over-expressed FBXW7 gene through plasmid vector in LNCaP and PC3 cell lines and the result shows that up-regulated FBXW7 can suppress the viability of PC cell through suppressing oncoproteins, such as c-MYC, NOTCH-1. After FBXW7 function experiment on PC cell, we knock-down LSD1 gene in the same kinds of cell lines. In western blot assay, we detected that down-regulation of LSD1 will cause the increasing of FBXW7 protein level and decreasing of its targeting oncoproteins. And mRNA level of FBXW7 did not change significantly after LSD1 knock-down, which means LSD1 may destabilize FBXW7 by protein-protein interactions. Moreover, exogenous wild type LSD1 and catalytically deficient mutant K661A both can abrogate previous effect of LSD1 knock-down. Consequently, LSD1 may promote PC cell survival by destabilizing FBXW7 without its demethylase-activity. Next, we compared two kinds inhibitors, and found that SP-2509 (Allosteric inhibitor) treatment suppress the cancer cell survival by blocking the LSD1–FBXW7 interaction, which is an effect that GSK-2879552 (catalytic inhibitor) cannot achieve. This work revealed a pivotal function of LSD1 in PCa, and indicated a new direction of LSD1 inhibitor research for PCa treatment.

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Regulation of Expression of Deoxyhypusine Hydroxylase (DOHH), the Enzyme That Catalyzes the Activation of eIF5A, by miR-331-3p and miR-642-5p in Prostate Cancer Cells

Journal of Biological Chemistry ◽

10.1074/jbc.m112.374686 ◽

2012 ◽

Vol 287 (42) ◽

pp. 35251-35259 ◽

Cited By ~ 31

Author(s):

Michael R. Epis ◽

Keith M. Giles ◽

Felicity C. Kalinowski ◽

Andrew Barker ◽

Ronald J. Cohen ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Growth ◽

Cancer Cells ◽

Cancer Cell ◽

Prostate Cancer Cell ◽

Translation Initiation Factor ◽

Initiation Factor ◽

Prostate Cancer Cells ◽

Normal Prostate ◽

Deoxyhypusine Hydroxylase

The enzyme deoxyhypusine hydroxylase (DOHH) catalyzes the activation of eukaryotic translation initiation factor (eIF5A), a protein essential for cell growth. Using bioinformatic predictions and reporter gene assays, we have identified a 182-nt element within the DOHH 3′-untranslated region (3′-UTR) that contains a number of target sites for miR-331-3p and miR-642-5p. Quantitative RT-PCR studies demonstrated overexpression of DOHH mRNA and underexpression of miR-331-3p and miR-642-5p in several prostate cancer cell lines compared with normal prostate epithelial cells. Transient overexpression of miR-331-3p and/or miR-642-5p in DU145 prostate cancer cells reduced DOHH mRNA and protein expression and inhibited cell proliferation. We observed synergistic growth inhibition with the combination of miR-331-3p and miR-642-5p and mimosine, a pharmacological DOHH inhibitor. Finally, we identified a significant inverse relationship between the expression of miR-331-3p or miR-642-5p and DOHH in a cohort of human prostate cancer tissues. Our results suggest a novel role for miR-331-3p and miR-642-5p in the control of prostate cancer cell growth via the regulation of DOHH expression and eIF5A activity.

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mTOR Complexes as a Nutrient Sensor for Driving Cancer Progression

International Journal of Molecular Sciences ◽

10.3390/ijms19103267 ◽

2018 ◽

Vol 19 (10) ◽

pp. 3267 ◽

Cited By ~ 16

Author(s):

Mio Harachi ◽

Kenta Masui ◽

Yukinori Okamura ◽

Ryota Tsukui ◽

Paul Mischel ◽

...

Keyword(s):

Amino Acid ◽

Cell Survival ◽

Cancer Cells ◽

Cancer Cell ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Cancer Metabolism ◽

Metabolic Reprogramming ◽

Cancer Cell Survival

Recent advancement in the field of molecular cancer research has clearly revealed that abnormality of oncogenes or tumor suppressor genes causes tumor progression thorough the promotion of intracellular metabolism. Metabolic reprogramming is one of the strategies for cancer cells to ensure their survival by enabling cancer cells to obtain the macromolecular precursors and energy needed for the rapid growth. However, an orchestration of appropriate metabolic reactions for the cancer cell survival requires the precise mechanism to sense and harness the nutrient in the microenvironment. Mammalian/mechanistic target of rapamycin (mTOR) complexes are known downstream effectors of many cancer-causing mutations, which are thought to regulate cancer cell survival and growth. Recent studies demonstrate the intriguing role of mTOR to achieve the feat through metabolic reprogramming in cancer. Importantly, not only mTORC1, a well-known regulator of metabolism both in normal and cancer cell, but mTORC2, an essential partner of mTORC1 downstream of growth factor receptor signaling, controls cooperatively specific metabolism, which nominates them as an essential regulator of cancer metabolism as well as a promising candidate to garner and convey the nutrient information from the surrounding environment. In this article, we depict the recent findings on the role of mTOR complexes in cancer as a master regulator of cancer metabolism and a potential sensor of nutrients, especially focusing on glucose and amino acid sensing in cancer. Novel and detailed molecular mechanisms that amino acids activate mTOR complexes signaling have been identified. We would also like to mention the intricate crosstalk between glucose and amino acid metabolism that ensures the survival of cancer cells, but at the same time it could be exploitable for the novel intervention to target the metabolic vulnerabilities of cancer cells.

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AKT-Independent Protection of Prostate Cancer Cells from Apoptosis Mediated through Complex Formation between the Androgen Receptor and FKHR

Molecular and Cellular Biology ◽

10.1128/mcb.23.1.104-118.2003 ◽

2003 ◽

Vol 23 (1) ◽

pp. 104-118 ◽

Cited By ~ 109

Author(s):

Pengfei Li ◽

Heehyoung Lee ◽

Shaodong Guo ◽

Terry G. Unterman ◽

Guido Jenster ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Cell Survival ◽

Cancer Cells ◽

Cancer Cell ◽

Cell Apoptosis ◽

Prostate Cancer Cell ◽

Transcriptional Analysis ◽

Prostate Cancer Cells ◽

Amino Terminal

ABSTRACT Recent studies suggested that the protection of cell apoptosis by AKT involves phosphorylation and inhibition of FKHR and related FOXO forkhead transcription factors and that androgens provide an AKT-independent cell survival signal in prostate cancer cells. Here, we report receptor-dependent repression of FKHR function by androgens in prostate cancer cells. Transcriptional analysis demonstrated that activation of the androgen receptor caused an inhibition of both wild-type FKHR and a mutant in which all three known AKT sites were mutated to alanines, showing that the repression is AKT independent. In vivo and in vitro coprecipitation studies demonstrated that the repression is mediated through protein-protein interaction between FKHR and the androgen receptor. Mapping analysis localized the interacting domains to the carboxyl terminus between amino acids 350 and 655 of FKHR and to the amino-terminal A/B region and the ligand binding domain of the receptor. Further analysis demonstrated that the activated androgen receptor blocked FKHR's DNA binding activity and impaired its ability to induce Fas ligand expression and prostate cancer cell apoptosis and cell cycle arrest. These studies identify a new mechanism for androgen-mediated prostate cancer cell survival that appears to be independent of the activity of the receptor on androgen response element-mediated transcription and establish FKHR and related FOXO forkhead proteins as important nuclear targets for both AKT-dependent and -independent survival signals in prostate cancer cells.

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The impact of Icariside II on human prostate cancer cell proliferation, mobility, and autophagy via PI3K-AKT-mTOR signaling pathway

10.21203/rs.3.rs-38587/v1 ◽

2020 ◽

Author(s):

Shuang Li ◽

Yunlu Zhan ◽

Yingwei Xie ◽

Yonghui Wang ◽

Yuexin Liu

Keyword(s):

Prostate Cancer ◽

Cell Cycle ◽

Cell Proliferation ◽

Cancer Cells ◽

Cancer Cell ◽

Prostate Cancer Cell ◽

Human Prostate ◽

Human Prostate Cancer ◽

Prostate Cancer Cells ◽

The Impact

Abstract Background The flavonol glycoside icariside Ⅱ (ICA II) has been shown to exhibit a range of anti-tumor properties. Herein we evaluated the impact of ICA II on the proliferation, motility, and autophagy activity of human prostate cancer cells, and we further evaluated the molecular mechanisms underlying these effects. Methods Herein, we treated DU145 human prostate cancer cells with a range of ICA II doses. We then evaluated the proliferative abilities of these cells via CCK-8 assay, whereas apoptosis and cell cycle status were assessed via flow cytometry. We further utilized wound healing and transwell assays to probe the impact of ICA II on migratory and invasive activities, while autophagy was assessed via laser confocal fluorescence microscopy. Western blotting was further utilized to measure LC3-II/I, Beclin-1, P70S6K, PI3K, AKT, mTOR, phospho-AKT, phospho-mTOR, and phospho-P70S6K levels, with RT-PCR being used to evaluate the expression of these same genes at the mRNA level. Results We found that ICA II was capable of mediating a dose- and time-dependent suppression of prostate cancer cell proliferative activity, while also causing these cells to enter a state of cell cycle arrest and apoptosis. We further determined that ICA II treatment was associated with significant impairment of prostate cancer cell migratory and invasive abilities, whereas autophagy was enhanced in treated cells relative to untreated controls. Levels of p-P70S6K, p-mTOR, p-AKT, and PI3K were all also decreased by ICA II. Conclusion Our results indicate that ICA II treatment is capable of suppressing human prostate tumor cell proliferation and disrupting migratory activity while enhancing autophagy through PI3K-AKT-mTOR signaling. As such, ICA II may be an ideal candidate drug for the treatment of prostate cancer.

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Expression and action of the growth hormone releasing peptide ghrelin and its receptor in prostate cancer cell lines

Journal of Endocrinology ◽

10.1677/joe.0.172r007 ◽

2002 ◽

Vol 172 (3) ◽

pp. R7-11 ◽

Cited By ~ 120

Author(s):

PL Jeffery ◽

AC Herington ◽

LK Chopin

Keyword(s):

Prostate Cancer ◽

Growth Hormone ◽

Cancer Cells ◽

Cell Lines ◽

Cancer Cell ◽

Prostate Cancer Cell ◽

Cancer Cell Lines ◽

Prostate Cancer Cells ◽

Normal Prostate ◽

Prostate Cancer Cell Lines

This study has examined the expression of two new facets of the growth hormone axis, the growth hormone secretagogue receptor (GHS-R) and its recently identified putative natural ligand ghrelin, in prostate cancer cells. GHS-R 1a and 1b isoforms and ghrelin mRNA expression were detected by RT-PCR in the ALVA-41, LNCaP, DU145 and PC3 prostate cancer cell lines. A normal prostate cDNA library expressed GHS-R1a, but not the 1b isoform or ghrelin. Immunohistochemical staining for the GHS-R 1a isoform and ghrelin was positive in the four cell lines studied. PC3 cells showed increased cell proliferation in vitro in response to ghrelin to levels 33% above untreated controls, implying a potential tumour-promoting role for ghrelin in this tissue. This study is the first to demonstrate the co-expression of the GHS-R and ghrelin in prostate cancer cells. It is also the first study to provide evidence that a previously unrecognised autocrine/paracrine pathway involving ghrelin, that is capable of stimulating growth, exists in prostate cancer.

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AMPA Receptor Antagonist CFM-2 Decreases Survivin Expression in Cancer Cells

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520618666180228123406 ◽

2018 ◽

Vol 18 (4) ◽

pp. 591-596 ◽

Cited By ~ 1

Author(s):

Domingo Sanchez Ruiz ◽

Hella Luksch ◽

Marco Sifringer ◽

Achim Temme ◽

Christian Staufner ◽

...

Keyword(s):

Cell Survival ◽

Receptor Antagonist ◽

Cancer Cells ◽

Glutamate Receptors ◽

Cancer Cell ◽

Ampa Receptor ◽

Ampa Receptors ◽

Survivin Expression ◽

Ampa Receptor Antagonist ◽

Cancer Cell Survival

Background: Glutamate receptors are widely expressed in different types of cancer cells. α-Amino-3- hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors are ionotropic glutamate receptors which are coupled to intracellular signaling pathways that influence cancer cell survival, proliferation, and migration. Blockade of AMPA receptors by pharmacologic compounds may potentially constitute an effective tool in anticancer treatment strategies. Method: Here we investigated the impact of the AMPA receptor antagonist CFM-2 on the expression of the protein survivin, which is known to promote cancer cell survival and proliferation. We show that CFM-2 inhibits survivin expression at mRNA and protein levels and decreases the viability of cancer cells. Using a stably transfected cell line which overexpresses survivin, we demonstrate that over-expression of survivin enhances cancer cell viability and attenuates CFM-2–mediated inhibition of cancer cell growth. Result: These findings point towards suppression of survivin expression as a new mechanism contributing to anticancer effects of AMPA antagonists.

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