Arrested Cell Cycle Progression Research Articles

CDKN2A/p16 evaluation in cytology specimens.

CDKN2A/p16 evaluation in cytology specimens.

Abstract 1421: Targeting ASPM suppresses the tumorigenicity of human hepatocellular carcinoma cells via ASPM-TPX2 axis disruption and result in increased chromosome segregation error

Abstract Aneuploidy and chromosomal instability (CIN) are common abnormalities in human cancer, might arise from a lesion in the chromosome segregation machinery. CIN has a tumour suppressive role because of excessive genomic damage and subsequent apoptosis or other forms of cell death. Therefore, induced massive chromosome instability and led to cellular death in cancer cells can be one of the most successful strategies for cancer therapy. ASPM is a critical regulator of cell-cycle progression, DNA damage and genome stability. In our previous work, we showed that ASPM was often overexpressed in human HCC and associated with tumor malignance progression and poor prognosis. However, the molecular roles of ASPM in the liver cancer cells still unclear. In this study, our results indicated that targeting ASPM caused a rising impaired chromosomal instability resulting in multinuclearity, mitosis progression prolong, increased multicentrosomes, chromosome segregation error and led to chromosome numbers variation in liver cancer cells. Finally, ASPM inhibition led to cell cycle progression arrest and apoptosis in liver cancer cells. Moreover, in vitro tumor spheroid assay and in vivo xenografts mouse model showed a therapeutic opportunity. Our results indicated the effect of ASPM silencing was led to chromosome segregation error in liver cancer cell. In mechanism analysis, the TPX2 was similar binary expression with ASPM in HCC and as downstream target. In our previous work, targeting TPX2 suppresses the tumorigenesis of hepatocellular carcinoma cells resulting in arrested mitotic phase progression and increased genomic instability. However, silenced ASPM or TPX2 both led to deregulated cyclin B2 protein expression. These results indicated ASPM-TPX2-Cyclin B2 axis was co-expression and TPX2-Cyclin B2 should be the potential downstream targets of ASPM. Moreover, in this study, ASPM was interacted with TPX2 and co-localized at mitotic spindle pore. Overexpression of EGFP-TPX2 was semi-restored the cell fitness caused by ASPM inhibition in liver cancer cells. Taken together, our results indicated that ASPM play important roles in cell proliferation, tumorigenesis and cell cycle progression in HCC cells. These results suggested a new insight into the mechanism of ASPM depletion through deregulated TPX2 and result in Cyclin B2 protein downregulation and contributed to cancer cell growth arrest, chromosome instability and cell death in hepatocellular carcinoma. Citation Format: Hung-Wei Pan, Zhong-Zhe Lin, Guan-Jin Huang. Targeting ASPM suppresses the tumorigenicity of human hepatocellular carcinoma cells via ASPM-TPX2 axis disruption and result in increased chromosome segregation error [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1421.

Natural Flavonoids in the Prevention and Treatment of Lung Cancer: A Pharmacological Aspect.

Deadly disease cancer has many types; among them, lung cancer is responsible for the highest number of cancer mortality. Existing therapies as well as drugs for treating lung cancer are not effective and are often associated with innumerable side effects and toxicities. For these reasons, researchers have been working on developing novel anti-cancer medicines from plants and other natural sources that have a high safety profile. Natural flavonoids are a polyphenolic group of phytochemicals extracted from plants and other plant-derived compounds. Natural flavonoids are gaining popularity due to their unique and priceless medicinal properties, including anticancer properties. Several researchers have already declared that flavonoids possess the ability to treat different cancers, particularly lung cancer. The bioactivity of natural flavonoids is mainly due to their structural diversity. Natural flavonoids fight against lung cancer by regulating redox homeostasis, upregulating apoptosis, pro-apoptotic factors, and survival genes, arresting cell cycle progression, autophagy, reducing cell proliferation and invasiveness, maintaining inflammation response, downregulating anti-apoptotic factors, and targeting lung cancer signaling pathways. Flavonoids can act alone or synergistically with other agents to treat lung cancer. Due to these reasons, it is possible to use natural flavonoids as pharmaceutical leads to prevent and treat lung cancer.

Ethanolic extract of Halymenia durvillei induced G2/M arrest and altered the levels of cell cycle regulatory proteins of MDA-MB-231 triple-negative breast cancer cells.

The GC-MS analysis reported n-hexadecanoic acid or palmitic acid as a major component of the ethanolic extract of Halymenia durvillei (HDET). This compound shows cytotoxic effects against various human cancer cells. The present study investigated the effect of HDET on the viability and proliferation of MDA-MB-231, a triple-negative breast cancer (TNBC) cell line. Cell proliferation and cell cycle analysis were determined by flow cytometry and cell cycle regulatory protein expression levels were then determined by Western blotting. The presence of reactive oxygen species (ROS) was evaluated by dichlorofluorescein, followed by analyzing changes in gene expression of antioxidant enzymes using a real-time polymerase chain reaction. HDET dose-dependently reduced cell viability with the 50% inhibitory concentration (IC50) of 269.4 ± 31.2 µg/mL at 24 h. The cell proliferation assays showed increased succinimidyl ester fluorescent intensity after treatment with ≥ 100 µg/mL of HDET, indicating the inhibition of cell proliferation. Cell cycle analysis using propidium iodide staining showed an increased percentage of cells in the G2/M phase. HDET also decreased the levels of cell cycle regulatory proteins including cyclin D1 and increased the level of p21. HDET promoted oxidative stress by increasing ROS levels along with the reduction of catalase expression. However, HDET did not induce apoptosis and caspase activation in TNBC cells. These findings suggest that HDET which is rich in palmitic acid may serve as a potential therapeutic agent to target TNBC via arrest cell cycle progression at the G2/M phase.

Metformin regulates myoblast differentiation through an AMPK-dependent mechanism.

This study aims to investigate how metformin (Met) affects muscle tissue by evaluating the drug effects on proliferating, differentiating, and differentiated C2C12 cells. Moreover, we also investigated the role of 5'-adenosine monophosphate-activated protein kinase (AMPK) in the mechanism of action of Met. C2C12 myoblasts were cultured in growth medium with or without Met (250μM, 1mM and 10mM) for different times. Cell proliferation was evaluated by MTT assay, while cell toxicity was assessed by Trypan Blue exclusion test and Lactate Dehydrogenase release. Fluorescence Activated Cell Sorting analysis was performed to study cell cycle. Differentiating myoblasts were incubated in differentiation medium (DM) with or without 10mM Met. For experiments on myotubes, C2C12 were induced to differentiate in DM, and then treated with Met at scalar concentrations and for different times. Western blotting was performed to evaluate the expression of proteins involved in myoblast differentiation, muscle function and metabolism. In differentiating C2C12, Met inhibited cell differentiation, arrested cell cycle progression in G2/M phase and reduced the expression of cyclin-dependent kinase inhibitor 1. These effects were accompanied by activation of AMPK and modulation of the myogenic regulatory factors. Comparable results were obtained in myotubes. The use of Compound C, a specific inhibitor of AMPK, counteracted the above-mentioned Met effects. We reported that Met inhibits C2C12 differentiation probably by blocking cell-cycle progression and preventing cells permanent exit from cell-cycle. Moreover, our study provides solid evidence that most of the effects of Met on myoblasts and myotubes are mediated by AMPK.

Fruit Extract of Sechium chinantlense (Lira & F. Chiang) Induces Apoptosis in the Human Cervical Cancer HeLa Cell Line.

Sechium edule (Cucurbitaceae) is a commercial species of chayote and is just one of several species in the genus Sechium, whose extracts inhibit proliferation in tumor cell lines. The capacity of the wild species Sechium chinantlense (SCH) as an antitumor agent is unknown, as is the mechanism of action. In the present study, HeLa cervical cancer and HaCaT normal cell lines were treated with SCH and cell proliferation was inhibited in both cell lines in a dose-dependent manner similar to the effect of the antineoplastic agent cisplatin (Cis). Additionally, SCH arrested cell cycle progression but only in HeLa cells and induced apoptosis, as shown by phosphatidylserine translocation and caspase-3 activation, while Cis did so in both cell lines. Exploration of the mechanism of action of SCH in HeLa cells suggests that apoptosis was mediated by the intrinsic signaling pathway since there was no activation of caspase-8, but there was a release of cytochrome-c. These findings suggest that the SCH extract has the potential to selectively kill tumor cells by promoting apoptosis, without harming nontumor cells.

Nanoengineered Gallium Ion Incorporated Formulation for Safe and Efficient Reversal of PARP Inhibition and Platinum Resistance in Ovarian Cancer.

Platinum-based chemotherapy remains the main systemic treatment of ovarian cancer (OC). However, the inevitable development of platinum and poly (adenosine diphosphate-ribose) polymerase inhibitor (PARPi) resistance is associated with poor outcomes, which becomes a major obstacle in the management of this disease. The present study developed "all-in-one" nanoparticles that contained the PARPi olaparib and gallium (Ga) (III) (olaparib-Ga) to effectively reverse PARPi resistance in platinum-resistant A2780-cis and SKOV3-cis OC cells and in SKOV3-cis tumor models. Notably, the olaparib-Ga suppressed SKOV3-cis tumor growth with negligible toxicity. Moreover, the suppression effect was more evident when combining olaparib-Ga with cisplatin or carboplatin, as evaluated in A2780-cis and SKOV3-cis cells. Mechanistically, the combined treatment induced DNA damage, which elicited the activation of ataxia telangiectasia mutated (ATM)/AMT- and Rad3-related (ATR) checkpoint kinase 1 (Chk1)/Chk2 signal transduction pathways. This led to the arrest of cell cycle progression at S and G2/M phases, which eventually resulted in apoptosis and cell death due to unrepairable DNA damage. In addition, effective therapeutic responses to olaparib-Ga and cisplatin combination or olaparib-Ga and carboplatin combination were observed in SKOV3-cis tumor-bearing animal models. Altogether, the present findings demonstrate that olaparib-Ga has therapeutic implications in platinum-resistant OC cells, and the combination of olaparib-Ga with cisplatin or carboplatin may be promising for treating patients with OC who exhibit resistance to both PARPi and platinum.

Multi-targeting TACE/ADAM17 and gamma-secretase of notch signalling pathway in TNBC via drug repurposing approach using Lomitapide

The aberrant expression of the Notch signalling pathway genes aids in potentiating the belligerent characteristics of numerous malignancies. Besides imparting abnormal proliferation and metastasis, the Notch also aids in the metabolic reprogramming of tumor cells. Since the activation of the Notch pathway is mediated via TACE/ADAM protease and the γ-secretase complex, hence it is crucial in determining a multi-targeted therapeutic approach to target these major proteases to downregulate the aberrant Notch signalling pathway. In this study, Lomitapide was chosen based on its binding score (−305.108 kJ/mol and − 173.174 kJ/mol) against the crucial proteases, TACE and γ-secretase, respectively. Further, the remarkable antitumor properties of Lomitapide were established on the TNBC cell lines (MDA-MB-231 and MDA-MB-468), along with the EMT-induced MDA-MB-468 cells. Apart from inducing ∼2 to 2.5-fold increase in the cellular ROS levels, Lomitapide treatment induced significant apoptosis, arrested cell cycle progression and reduced sphere and colony forming abilities of the TNBC cells. Differentiated epithelial phenotype with diminished CD44-stem cell marker was also observed upon treatment. Furthermore, reduction of migration potential, decrease in the gene expression profile of the EMT markers, along with downregulation of the Notch signalling genes were evident in the treated TNBC cells. Altogether, the present study attributes the repurposing of Lomitapide as an effective therapeutic agent against the major proteases of the Notch pathway to combat TNBC progression and dissemination.

Integrated network pharmacology and experimental verification to investigate the mechanisms of YYFZBJS against colorectal cancer via CDK1/PI3K/Akt signaling.

Colorectal cancer (CRC) is a common digestive tract malignancy with rising incidence and morbidity worldwide during recent years. Yi-Yi-Fu-Zi-Bai-Jiang-San (YYFZBJS), a traditional Chinese medicine formula, has showed positive effects against cancers. However, the mechanisms underlying its anticancer effects requires investigation. Information on bioactive compounds, potential YYFZBJS targets, and CRC-associated genes, was obtained from public databases. The key targets and ingredients as well their corresponding signaling pathways were identified using bioinformatic approaches, including Kyoto encyclopedia of genes and genomes (KEGG) analyses, gene ontology (GO), and protein-protein interaction (PPI). Subsequently, molecular docking was used to verify the main compounds-targets. Potential YYFZBJS therapeutic effects against CRC were validated in vitro and in vivo. Using pharmacological network analysis, 40 YYFZBJS active compounds and 21 potential anti-CRC targets were identified. YYFZBJS was an important regulator of CRC through various targets and signaling pathways, particularly the cell cycle and PI3K/AKT pathway. Additionally, YYFZBJS suppressed the proliferation of CRC cells. Flow cytometry showed that YYFZBJS induced apoptosis and cell cycle arrest in the G2/M phase. Western blotting analysis indicated that YYFZBJS reduced the protein levels of CDK1, p-AKT, and p-PI3K, without altering total PI3K and AKT protein levels. In vivo analysis found that YYFZBJS inhibited tumor growth and PI3K/AKT signaling in a mouse model of CRC. As predicted by network pharmacology and validated by the experimental results, YYFZBJS inhibited proliferation, induced apoptosis and arrested cell cycle progression in CRC by modulating the CDK1/PI3K/Akt signaling pathway.

FGFR1OP2 Promotes Proliferation and Survival of Myeloma Cells and Is a Potential Therapeutic Target

Background: Multiple myeloma (MM) is an incurable disease with high tendency to relapse and drug resistance. Exploring new targets and new drugs is crucial for treatment. Elevated expression of fibroblast growth factor receptor 1 oncogene partner 2 （FGFR1OP2） has been observed in relapsed and refractory MM and indicated the poor prognosis. FGFR1OP2 is expressed in diverse tissues, including bone marrow, spleen and thymus and might be a oncogene in lung cancer, acute leukemia. we hypothesize that FGFR1OP2 may exert effects in MM and will be a a potential therapeutic target. Aims: To Investigate the functional role of FGFR1OP2 in MM Methods: FGFR1OP2 knockdown and overexpression MM cell lines were generated. Molecular mechanism underlying was elucidated by qRT-PCR, Western Blot and gene expression microarray. Results: To study whether FGFR1OP2 is important for MM, we found high expression of FGFR1OP2 in different myeloma cell lines which was validated by CCLE datasets. Knockdown the FGFR1OP2 in MM cells led to a decreased proliferation, while overexpression of FGFR1OP2 increased the cell growth (Fig.1a). Next, flow cytometry was performed to evaluate the cell cycle and apoptosis in MM cells. FGFR1OP2 suppression showed cell cycle arrest and overexpression accelerateed cell cycle progression (Fig.1b). Furthermore, Bortezomib(Bor)-induced apoptosis of MM cells was significantly increased when FGFR1OP2 expression was suppressed (Fig.1c). Moreover, results of Western Blot revealed increased levels of Bor-induced caspase-3 and cleaved PARP after FGFR1OP2 knockdown. Taken together these data indicate that FGFR1OP2 can increase MM cell growth and inhibit apoptosis. To better understand the molecular mechanism of FGFR1OP2, we performed gene expression microarray profiling and compared results from FGFR1OP2-knockdown cells and control cells. Surprisingly, data showed that the expression of several members of the Hippo signaling pathway changed significantly. We performed Western Blot to validate these results, and found expression of YAP1 decreased while MST1/2 increased in FGFR1OP2-knockdown cells (Fig.1c). This suggests that the FGFR1OP2 promotes MM cell growth and anti-apoptosis through Hippo signaling pathway. Conclusion:FGFR1OP2 is critical for the proliferation and survival of MM cells through Hippo pathway and may represent a novel target for therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

New NNN pincer copper complexes as potential anti-prostate cancer agents

Eleven novel NNN Cu(II) complexes supported by a tridentate bis(imidazo[1,2-α]pyridin-2-yl)pyridine ligand were synthesized and characterized by elemental analysis, HRMS, and X-ray determination. Target prediction and docking studies indicated that these pincer complexes formed hydrogen bonds with Asp33 and Gly35 of Cathepsin D protein, which is highly associated with prognosis of advanced prostate cancer. Furthermore, they exhibited anti-proliferation activity in both androgen-sensitive and androgen-insensitive prostate cancer cells according to WST-1 assay results. Mechanistic study showed that pincer complexes arrested cell cycle progression at G0/G1 phase and inhibited Cathepsin D regulated signaling pathways. Most importantly, new pincer copper complexes significantly inhibited xenograft prostate cancer growth along with a promising in vivo safety profile. In summary, these results suggest the applicability of the developed novel pincer copper complexes as promising anticancer agents for prostate cancer treatment.

Molecular mechanisms of bilirubin induced G1 cell cycle arrest and apoptosis in human breast cancer cell lines: involvement of the intrinsic pathway.

Bilirubin, as an essential constituent of cellular signaling pathways, may have a role in cell growth and apoptosis in breast cancer, although the biochemical relevance is still unclear. The purpose of the present study is to recognize the mechanism underlying bilirubin-induced apoptosis in breast cancer cell lines. To detect the cell viability, MTT assay was carried out. Apoptosis was assessed by flow cytometry analysis and caspase activities were determined by colorimetric method. The expression of AhR, cyclin D1, cyclin A, p53, p27, Bcl-2, and Bax were examined using real-time PCR. The cell viability has been reduced by bilirubin in a dose-dependent manner and an intrinsic apoptotic response has been occurred that was evidenced by the elevation of caspase-3 and - 9 activities. Bilirubin induced cell arrest in cell-cycle progression, which was associated with the induction of AhR expression, down-regulation of cyclin D1, cyclin A, and upregulation of p53 and p27 expression. Following bilirubin treatment, Bcl-2 was decreased and Bax protein was increased in both cell lines. To discuss, bilirubin, as a naturally occurring antiproliferative molecule, mediates growth inhibition by induction of cell cycle arrest and apoptosis in MCF-7 and MDA-MB-468 breast cancer cells. It is associated with the suppression of cyclin A, D1, and Bcl-2; induction of p53, p27, and Bax together with the activation of caspase-3 and - 9.

Methanol extraction revealed anticancer compounds Quinic Acid, 2(5H)‑Furanone and Phytol in Andrographispaniculata.

Andrographis paniculata (Ap) has been a part of traditional medicine for its anti-inflammatory effects, treatment of snake bites and liver abnormalities. Several investigations have revealed its bioactive components to be andrographolides. The methanolic extracts of leaves from Ap were characterized, the non-andrographolides were identified and screened for anti-proliferative activity. The extracts showed significant toxicity against numerous cancer cells including HeLa, MCF7, BT549, 293 and A549 cells. Anti-proliferative activity and effect on cancer cell invasion (metastatic potential) and cell migration were examined. The extracts revealed significant inhibition of the ability of HeLa cells in repairing the gap created by a vertical wound made on a confluent cell monolayer. Similarly, a 40% reduction in cell migration was observed in presence of the extracts. Significant anti-angiogenic activity in terms of reduced blood capillary formation was observed on the Chorioallantoic membranes of embryonated hen eggs co-inoculated with HeLa cells and the extracts. Analysis of HeLa cells treated with the extracts using flow cytometry indicated the arrest of cell cycle progression at the G2/M phase. Variation in the Bax/Bcl-2 ratio and elevated caspase-3 levels by immunoblotting confirmed cell death induction via the apoptotic pathway. Investigation of the extracts by gas chromatography-mass spectrometry displayed the predominant components to be 2(5H)-Furanone (14.73%), Quinic acid (17.32%), and Phytol (11.43%). These components have been previously known to have anticancer activity, while being studied individually in other plants. This is the first study, to the best of our knowledge, on the anti-proliferative and anti-angiogenic activity of the non-andrographolide components from Ap.

IL23 suppresses proliferation and promotes apoptosis of human granulosa-like tumor cell line KGN by targeting the androgen receptor signal pathway

Background: Polycystic ovary syndrome (PCOS) is associated with chronic low-grade inflammation. IL23 is a classic pro-inflammatory factor, which has been found that serum levels of IL23 were higher in patients with PCOS. However, the exact function of IL23 in regulating the pathogenesis of PCOS has not been elucidated. This study aimed to investigate the role of IL23 in the pathogenesis of PCOS and uncover the possible molecular mechanism. Methods: We investigated the role of IL23 in the proliferation, cell cycle progression and apoptosis of granulosa cells (GCs) using the human granulosa-like tumor cell line KGN. Results: IL23 suppressed the proliferation, arrested cell cycle progression, and increased apoptosis of KGN cells. We also found that IL23 decreases proliferation and promotes apoptosis in KGN cells is mediated by androgen receptor (AR) signaling. Conclusions: Our results demonstrated that IL23 suppressed cell proliferation and promoted apoptosis of KGN cells, which might provide new evidence for abnormal proliferation and apoptosis of GCs in PCOS.

Hsa_circ_0044907 promotes acute myeloid leukemia progression through upregulating oncogene KIT via sequestering miR-186-5p

ABSTRACT Background: It has been reported that circular RNA hsa_circ_0044907 (circ_0044907) expression is overtly elevated in acute myeloid leukemia (AML) patient-derived BMMCs. However, the effect of circ_0044907 on AML progression remains un-clarified. Methods: Expression of circ_0044907 in BM and AML cells were detected with real-time quantitative reverse transcription-polymerase chain reaction (RT-qPCR). Cell viability, proliferation, apoptosis, and cycle progression were determined by 3-(4,5-Dimethylthiazol-2-yl)−2,5-Diphenyltetrazolium Bromide (MTT), 5-ethynyl-2’-deoxyuridine (EDU), and flow cytometry assays. The regulatory mechanism of circ_0044907 was predicted by bioinformatics analysis and validated by dual-luciferase reporter, RNA pull-down, and RNA immunoprecipitation (RIP) assays. In vivo experiments were carried out to verify the function of circ_0044907. Results: Circ_0044907 was overexpressed in AML patient-derived BM and AML cells. Furthermore, circ_0044907 could distinguish AML patients from healthy controls, and high circ_0044907 expression in BM had a poor prognosis for AML patients, implying that circ_0044907 served as a diagnostic and prognostic indicator for AML. Functionally, circ_0044907 silencing reduced cell viability, restrained cell proliferation, arrested cell cycle progression, and induced cell apoptosis in AML cells in vitro. Furthermore, circ_0044907 knockdown decreased AML cell growth in xenograft mouse models. Mechanically, circ_0044907 sponged miR-186-5p to block the inhibiting effect of miR-186-5p on KIT. Silenced miR-186-5p expression weakened circ_0044907 knockdown mediated suppression on AML cell viability, proliferation, and cycle progression. Also, forced KIT expression weakened miR-186-5p upregulation mediated inhibition on AML cell viability, proliferation, and cycle progression. Conclusion: Circ_0044907 absorbed miR-186-5p to block the inhibiting impact of miR-186-5p on KIT, thus promoting AML progression.

Selective cell cycle arrest in glioblastoma cell lines by quantum molecular resonance alone or in combination with temozolomide

BackgroundGlioblastoma is the most aggressive form of brain cancer, characterised by high proliferation rates and cell invasiveness. Despite advances in surgery and radio-chemotherapy, patients continue to have poor prognoses, with a survival rate of 14–15 months. Thus, new therapeutic strategies are needed. Non-ionising electromagnetic fields represent an emerging option given the potential advantages of safety, low toxicity and the possibility to be combined with other therapies.MethodsHere, the anticancer activity of quantum molecular resonance (QMR) was investigated. For this purpose, three glioblastoma cell lines were tested, and the QMR effect was evaluated on cancer cell proliferation rate and aggressiveness. To clarify the QMR mechanism of action, the proteomic asset after stimulation was delineated. Mesenchymal stromal cells and astrocytes were used as healthy controls.ResultsQMR affected cancer cell proliferation, inducing a significant arrest of cell cycle progression and reducing cancer tumorigenicity. These parameters were not altered in healthy control cells. Proteomic analysis suggested that QMR acts not only on DNA replication but also on the machinery involved in the mitotic spindle assembly and chromosome segregation. Moreover, in a combined therapy assessment, QMR significantly enhanced temozolomide efficacy.ConclusionsQMR technology appears to be a promising tool for glioblastoma treatment.

ARV-771 Acts as an Inducer of Cell Cycle Arrest and Apoptosis to Suppress Hepatocellular Carcinoma Progression.

Hepatocellular carcinoma (HCC) is the most commonly diagnosed liver cancer with limited treatment options and extremely poor prognosis worldwide. Recently, the proteolysis targeting chimeras (PROTACs), which aim to induce proteasome-mediated degradation of interesting proteins via recruiting E3 ligases, have become the advanced tools and attractive molecules for cancer treatment. However, the anticancer effects of PROTACs in HCC remain to be clarified. Here, we evaluate the anticancer activity of ARV-771, a previously reported PROTAC compound designed for bromodomain and extra-terminal domain (BET) proteins, in HCC. We show that ARV-771 suppresses the cell viability and colony formation of HCC cells via arresting cell cycle progression and triggering apoptosis. Further investigations reveal that ARV-771 notably downregulates multiple non-proteasomal deubiquitinases which are critical to the development of cancers. Additionally, HCC cells can decrease their sensitivity to ARV-771 via activating the MEK/ERK and p38 MAPKs. ARV-771 also inhibits HCC progression in vivo. Moreover, we show that ARV-771 and sorafenib, a Raf inhibitor that clinically used for targeted therapy of liver cancer, can synergistically inhibit the growth of HCC cells. Overall, this study not only explores the anticancer activity of ARV-771 and its underlying mechanisms in HCC, but also deepens our understanding of deubiquitinases, MAPKs, cell cycle, and apoptosis induction in cancer therapy.

Ribosome assembly factor PNO1 is associated with progression and promotes tumorigenesis in triple‑negative breast cancer.

The aim of the present study was to investigate the expression of ribosome assembly factor partner of NOB1 homolog (PNO1) and its association with the progression of breast cancer (BC) in patients, as well as its biological function and underlying mechanism of action in BC cells. Bioinformatics and immunohistochemical analyses revealed that PNO1 expression was significantly increased in BC tissues and its high mRNA expression was associated with shorter overall survival (OS) and relapse-free survival (RFS) of patients with BC, as well as multiple clinical characteristics (including advanced stage of NPI and SBR, etc.) of patients with BC. Biological functional studies revealed that transduction of lentivirus encoding sh-PNO1 significantly downregulated PNO1 expression, reduced cell confluency and the number of BC cells in vitro and inhibited tumor growth in vivo. Moreover, PNO1 knockdown decreased the cell viability and arrested cell cycle progression at the G2/M phase, as well as downregulated cyclin B1 (CCNB1) and cyclin-dependent kinase 1 (CDK1) protein expression in BC cells. Correlation analysis demonstrated that PNO1 expression was positively correlated with both CDK1 and CCNB1 expression in BC samples. Collectively, PNO1 was upregulated in BC and associated with BC patient survival, and PNO1 knockdown suppressed tumor growth in vitro and in vivo. In addition, positive regulation of CCNB1 and CDK1 may be one of the underlying mechanisms.

Novel insights into the anti-cancer effects of 3-bromopyruvic acid against castration-resistant prostate cancer

3-bromopyruvic acid (3-BP), a small molecule alkylating agent, has been emerged as a glycolytic inhibitor with anticancer activities. However, the effects of 3-BP on the growth and metastasis in prostate cancer have not been well investigated. Here we investigated the anti-cancer effects of 3-BP on prostate cancer in vitro and in vivo. Cell growth, apoptosis, migration, motility, and invasion were examined. The tumor growth ability was determined using a xenograft murine model. Transcriptome analysis using RNA-seq was performed to explore the mechanism of action of 3-BP. Our experimental results showed that 3-BP effectively inhibits prostate cancer cell growth, especially in castration-resistant prostate cancer (CRPC) cells. Moreover, 3-BP induces apoptosis and suppresses cell migration, motility, epithelial-mesenchymal transition (EMT), and invasion in CRPC cells. In addition, 3-BP also attenuates tumor growth in a xenograft murine model. Through transcriptome analysis using RNA-seq, 3-BP significantly regulates the cell cycle pathway and decreases the expression of downstream cycle cycle-associated genes in CRPC cells. The results of cell cycle analysis indicated that 3-BP arrests cell cycle progression at G2/M in CRPC cells. These results suggest that 3-BP has the potential in inhibiting CRPC progression and might be a promising drug for CRPC treatment.

The HOG pathway and the regulation of osmoadaptive responses in yeast.

Cells coordinate intracellular activities in response to changes in the extracellular environment to maximize their probability of survival and proliferation. Eukaryotic cells need to adapt to constant changes in the osmolarity of their environment. In yeast, the high-osmolarity glycerol (HOG) pathway is responsible for the response to high osmolarity. Activation of the Hog1 stress-activated protein kinase (SAPK) induces a complex program required for cellular adaptation that includes temporary arrest of cell cycle progression, adjustment of transcription and translation patterns, and the regulation of metabolism, including the synthesis and retention of the compatible osmolyte glycerol. Hog1 is a member of the family of p38 SAPKs, which are present across eukaryotes. Many of the properties of the HOG pathway and downstream-regulated proteins are conserved from yeast to mammals. This review addresses the global view of this signaling pathway in yeast, as well as the contribution of Dr Hohmann's group to its understanding.