SIRT3 inhibits prostate cancer by destabilizing oncoprotein c-MYC through regulation of the PI3K/Akt pathway.
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ABSTRACT:
SUBMITTER: Quan Y
PROVIDER: S-EPMC4694917 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background/aimProstate cancer (PCa) is the most commonly diagnosed genital cancer in men globally. Among patients who develop advanced PCa, 80% are affected by bone metastasis, with a sharp drop in survival rate. Despite efforts, the details of mechanisms of metastasis of PCa remain unclear. SIRT5, an NAD+-dependent deacylase, is hypothesized to be a crucial regulator of various cancers. The role of SIRT5 in cancer has not been extensively studied compared to other SIRTs. In this study, we showed significantly decreased levels of SIRT5 in PC-3M, a highly aggressive PC-3 cell variant.Materials and methodsWe characterized the differentially expressed proteins between parental and SIRT5 KO PC-3 cells using quantitative proteomics analysis.ResultsA significant increase in expression of interleukin-1β (IL-1β) in SIRT5 KO cells was observed, and the PI3K/AKT/NF-ĸB signaling pathway was found significantly elevated in SIRT5 KO cells by the Gene Ontology annotation and KEGG pathway functional enrichment analysis. Moreover, we confirmed that SIRT5 can bind PI3K by immunoprecipitation analysis.ConclusionThis study is the first to demonstrate a relationship between SIRT5 and PCa metastasis, suggesting that SIRT5-mediated inhibition of the PI3K/AKT/NK-kB pathway is reduced for secondary metastasis from bone to other tissues.
| S-EPMC8717960 | biostudies-literature
Project description:DT-13, a saponin monomer 13 from the dwarf lilyturf tuber, was reported to exhibit anti-inflammatory, hepatoprotective, cardioprotective as well as antitumor activities in a number of tumor cells. Prostate cancer is the second leading cause of cancer death in males, discovery of novel antitumor drug for therapy of prostate cancer is expected. Aiming to evaluate whether DT-13 could become a candidate to treat prostate cancer, we recently investigated the antitumor effect of DT-13 on human prostate cancer cells and the underlying mechanism. DT-13 was found to effectively inhibit proliferation and metastasis of prostate cancer PC3 and DU145 cell lines in a dose-dependent manner. Treatment by DT-13 resulted in a mitochondria-mediated apoptosis, which was accompanied by the chromatin condensation and nuclear shrinkage in the prostate cancer cells. Moreover, DT-13 caused remarkable upregulation of Bax, Bad, Cytochrome C, cleaved -caspase 3, -caspase 9 and -PARP, in contrast to the downregulation of Bcl-2. Nevertheless, no obvious change in intracellular ROS level was observed after DT-13 treatment. We further demonstrated that DT-13 could inhibit PC3 cell metastasis in which suppression of Integrinβ1 and MMP2/9 might be involved. Western blot analysis indicated DT-13 significantly decreased the phosphorylation of PDK1, Akt, mTOR as well as p70S6K, suggesting the pro-apoptotic and anti-metastatic effects of DT-13 on prostate cancer cells might be attributed to the blockade of PI3K/Akt pathway. Collectively, our findings suggest DT-13 is worthy of further investigation as a drug candidate for the treatment of prostate cancer.
| S-EPMC6292965 | biostudies-literature
Project description:BackgroundProstate cancer (PCa) is a malignancy with high incidence and the principal cause of cancer deaths in men. GATA binding protein 5 (GATA5) belongs to the GATA gene family. GATA5 has a close association with carcinogenesis, but the role of GATA5 in PCa remains poorly understood. The aim of our present study was to probe into the effect of GATA5 on PCa progression and to elucidate the involved mechanism.MethodsThe expression of GATA5 was detected in both PCa samples and PCa cell lines. GATA5 overexpression, PLAGL2 knockdown, and overexpression cell models were generated, then Western blotting experiments were utilized to validate the efficiency of transfection. The effects of GATA5 on PCa cell proliferation, metastasis, apoptosis, cell cycle progression, and EMT were detected in vitro or in vivo. Furthermore, the mechanism by which GATA5 inhibits prostate cancer progression through regulating PLAGL2 via the FAK/PI3K/AKT pathway was also explored.ResultsGATA5 expression was downregulated in PCa samples and cell lines. GATA5 overexpression inhibited PCa cell proliferation and metastasis but increased the rate of apoptosis. In addition, we confirmed that GATA5 inhibited prostate cancer progression, including EMT, by regulating PLAGL2 via the FAK/PI3K/AKT pathway.ConclusionWe demonstrated that GATA5, as a tumor suppressor in PCa, inhibits PCa progression by regulating PLAGL2. These results showed that the GATA5/PLAGL2/FAK/PI3K/AKT pathway may become a new therapeutic direction for the treatment of PCa.
| S-EPMC9099954 | biostudies-literature
Project description:Using a panel of cancer cell lines, we characterized a novel degrader of AKT, MS21. In mutant PI3K-PTEN pathway cell lines, AKT degradation was superior to AKT kinase inhibition for reducing cell growth and sustaining lower signaling over many days. AKT degradation, but not kinase inhibition, profoundly lowered Aurora kinase B (AURKB) protein, which is known to be essential for cell division, and induced G2-M arrest and hyperploidy. PI3K activated AKT phosphorylation of AURKB on threonine 73, which protected it from proteasome degradation. A mutant of AURKB (T73E) that mimics phosphorylation and blocks degradation rescued cells from growth inhibition. Degrader-resistant lines were associated with low AKT phosphorylation, wild-type PI3K/PTEN status, and mutation of KRAS/BRAF. Pan-cancer analysis identified that 19% of cases have PI3K-PTEN pathway mutation without RAS pathway mutation, suggesting that these patients with cancer could benefit from AKT degrader therapy that leads to loss of AURKB.SignificanceMS21 depletes cells of phosphorylated AKT (pAKT) and a newly identified AKT substrate, AURKB, to inhibit tumor growth in mice. MS21 is superior to prior agents that target PI3K and AKT due to its ability to selectively target active, pAKT and sustain repression of signaling to deplete AURKB. This article is highlighted in the In This Issue feature, p. 2945.
| S-EPMC9056008 | biostudies-literature
Project description:ObjectiveThe objective of this study was to investigate the inhibitory effect of sophocarpine on the progression of castration-resistant prostate cancer (CRPC) and the underlying molecular mechanism.MethodsDU145 and PC3 cells (two CRPC cell lines), incubated with different concentrations of sophocarpine, were used. Cell Counting Kit-8 assay, real-time cellular analysis, and colony formation assay were conducted to evaluate the proliferation of CRPC cells. Cytometry flow analysis was performed to evaluate the apoptosis rate of CRPC cells. Wound healing and Transwell invasion assays were performed and the levels of the epithelial-mesenchymal transition (EMT)-related proteins were determined to analyze cell migration and invasion abilities. A xenografted tumor model of nude mice was used to examine the anti-cancer effect of sophocarpine on CRPC. Western blotting was performed to evaluate the activities of the PI3K/AKT/mTOR signaling pathway both in cells and tumor tissues.ResultsIn vitro tests showed that sophocarpine suppressed the proliferation of CRPC cells, reduced the migration and invasion abilities, and increased the apoptosis rate. In vivo, sophocarpine decreased the weight and volume of tumor tissues. Mechanically, sophocarpine exerted its anti-cancer effects by inactivating PI3K/AKT/mTOR signaling.ConclusionSophocarpine inhibited the progression of CRPC by downregulating the PI3K/AKT/mTOR signaling pathway and showed a potential to be an anti-cancer agent against CRPC.
| S-EPMC9484452 | biostudies-literature
Project description:MicroRNAs (miRNAs) are short, conserved segments of non-coding RNA which play a significant role in prostate cancer development and progression. To identify miRNAs associated with castration resistance, we performed miRNA microarray analysis comparing castration resistant prostate cancer (CRPC) with androgen dependent prostate cancer (ADPC). We identified common underexpression of miR-4638-5p in CRPC compared to ADPC samples, which were further confirmed by quantitative PCR analysis. The role of miR-4638-5p in prostate cancer androgen-independent growth has been demonstrated both in vitro and in vivo. We also identified Kidins220 as a target gene directly regulated by miR-4638-5p and shRNA-mediated knockdown of Kidins220 phenocopied miR-4638-5p restoration. Subsequently, we revealed that Kidins220 activates PI3K/AKT pathway, which plays a key role in CRPC. Loss of miR- 4638-5p may lead to CRPC through the activity of Kidins220 and PI3K/AKT pathway. Furthermore, we found that miR-4638-5p, through regulating Kidins220 and the downstream activity of VEGF and PI3K/AKT pathway, influences prostate cancer progression via angiogenesis. The identification of miR-4638-5p down-regulation in CRPC and the understanding of the functional role of miR-4638-5p and its downstream genes/pathways have the potential to develop biomarkers for CRPC onset and to identify novel targets for novel forms of treatments of this lethal form of PCa.
| S-EPMC5216953 | biostudies-literature
Project description:LZTFL1 is a tumor suppressor located in chromosomal region 3p21.3 that is deleted frequently and early in various cancer types including the kidney cancer. However, its role in kidney tumorigenesis remains unknown. Here we hypothesized a tumor suppressive function of LZTFL1 in clear cell renal cell carcinoma (ccRCC) and its mechanism of action based on extensive bioinformatics analysis of patients' tumor data and validated it using both gain- and loss-functional studies in kidney tumor cell lines and patient-derive xenograft (PDX) model systems. Our studies indicated that LZTFL1 inhibits kidney tumor cell proliferation by destabilizing AKT through ZNRF1-mediated ubiquitin proteosome pathway and inducing cell cycle arrest at G1. Clinically, we found that LZTFL1 is frequently deleted in ccRCC. Downregulation of LZTFL1 is associated with a poor ccRCC outcome and may be used as prognostic maker. Furthermore, we show that overexpression of LZTFL1 in PDX via lentiviral delivery suppressed PDX growth, suggesting that re-expression of LZTFL1 may be a therapeutic strategy against ccRCC.
| S-EPMC10039360 | biostudies-literature
Project description:Gallbladder cancer is the most common malignant tumor of the biliary system and is characterized by difficulty to diagnose in early stages, a high degree of malignancy, and poor prognosis. Finding new drugs may improve the prognosis for this dismal cancer. Herein, we investigated the potential application of pterostilbene (PTS) against gallbladder cancer in vivo and in vitro. PTS potently inhibited cell proliferation, migration and invasion of gallbladder cancer cells. Moreover, PTS also had a function of inducing apoptosis in vitro. Meanwhile, PTS reversed EMT with a correlated inhibition of PI3K/Akt activation. Tumor xenograft models showed that PTS inhibited tumor growth and had low toxicity in vivo, which were consistent with the in vitro data. These findings indicate that PTS arrests cell growth through inhibition of PI3K/AKT signaling and is a potential drug for the therapy of gallbladder cancer.
| S-EPMC7902850 | biostudies-literature
Project description:Metastasis remains the primary cause of prostate cancer (CaP)-related death. Using a genome wide shRNA screen, we identified GABARAPL1 as a potential CaP metastasis suppressor. GABARAPL1 mRNA levels inversely correlate with the invasive potential of a panel of human CaP cell lines. Lower mRNA levels correlate with higher Gleason scores in clinical CaP tumor samples. Moreover, Kaplan-Meier curves analysis showed that GABARAPL1 down-regulation in cancer tissues is associated with decreased disease-free survival in CaP patients. Knockdown of GABARAPL1 in human LNCaP cells results in increased invasion in vitro and lymph node metastasis in vivo. Vice versa, ectopic expression of GABARAPL1 decreases the invasiveness of CWR22Rv1 cells. Our previous in vitro shRNA screening identified FOXO4, a PI3K/Akt-inactivating downstream target, as a potential CaP metastasis suppressor. We show here that silencing FOXOs leads to reduced GABARAPL1 expression and enhanced invasion in LNCaP cells. Transfection of constitutively-activated Akt (myr-Akt) increased the invasion of LNCaP cells, which is associated with the inactivation of FOXOs and decreased GABARAPL1 expression. Indeed, forced expression of GABARAPL1 reversed the increased invasiveness of LNCaP/myr-Akt cells. Finally, immunohistochemistry analysis shows that Akt phosphorylation is negatively correlated with GABARAPL1 expression in human CaP tissues. Taken together, our data indicate that the suppression of FOXOs-GABARAPL1 signaling by Akt is an important mechanism for CaP progression and metastasis.
| S-EPMC5354845 | biostudies-literature
Project description:BackgroundClear cell renal cell carcinoma (ccRCC) is the most common and aggressive type of renal malignancy. Methyltransferase like 13 (METTL13) functions as an oncogene in most of human cancers, but its function and mechanism in ccRCC remains unreported.MethodsqRT-PCR, western blotting and immunohistochemistry were used to detect METTL13's expression in tissues. The effects of METTL13 on ccRCC cells' growth and metastasis were determined by both functional experiments and animal experiments. Weighted gene co-expression network analysis (WGCNA) was performed to annotate METTL13's functions and co-immunoprecipitation (co-IP) was used to determine the interaction between METTL13 and c-Myc.ResultsMETTL13 was underexpressed in ccRCC tissues compared to normal kidney tissues and its low expression predicted poor prognosis for ccRCC patients. The in vitro studies showed that knockdown and overexpression of METTL13 respectively led to increase and decrease in ccRCC cells' proliferation, viability, migratory ability and invasiveness as well as epithelial-mesenchymal transition (EMT). The in vivo experiment demonstrated the inhibitory effect that METTL13 had on ccRCC cells' growth and metastasis. Bioinformatic analyses showed various biological functions and pathways METTL13 was involved in. In ccRCC cells, we observed that METTL13 could negatively regulate PI3K/AKT/mTOR/HIF-1α pathway and that it combined to c-Myc and inhibited c-Myc protein expression.ConclusionsIn general, our finding suggests that high expression of METTL13 is associated with favorable prognosis of ccRCC patients. Meanwhile, METTL13 can inhibit growth and metastasis of ccRCC cells with participation in multiple potential molecular mechanisms. Therefore, we suggest METTL13 can be a new diagnostic and therapeutic target for ccRCC in the future.
| S-EPMC8120818 | biostudies-literature