AKIP1 promotes cell proliferation, invasion, stemness and activates PI3K-Akt, MEK/ERK, mTOR signaling pathways in prostate cancer

2021 ◽  
Author(s):  
Jiabin Zhao ◽  
Binjiahui Zhao ◽  
Limin Hou
Keyword(s):  
Prostate Cancer ◽  
Cell Proliferation ◽  
Signaling Pathways ◽  
Cancer Patients ◽  
Rna Sequencing ◽  
Mtor Signaling ◽  
Sequencing Analysis ◽  
Lncap Cells ◽  
Oncogenic Signaling ◽  
Interacting Protein

Abstract Background: The study aimed to examine the molecular mechanism and clinical significance of A-kinase interacting protein 1 (AKIP1) in prostate cancer. Methods: The effect of AKIP1 on cell proliferation, migration, invasion, apoptosis and stemness was determined by overexpressing and knocking down AKIP1 in LNCaP and 22Rv1 cells via lentivirus infection. Furthermore, differentially expressed genes (DEGs) by AKIP1 modification were determined using RNA sequencing. Besides, the correlation of AKIP1 with clinicopathological features and prognosis in 130 prostate cancer patients was assessed. Results: AKIP1 expression was increased in VCaP, LNCaP, DU145 cells while similar in 22Rv1 cells compared with RWPE-1 cells. Furthermore, AKIP1 overexpression promoted 22Rv1 and LNCaP cell proliferation, invasion, but inhibited apoptosis; meanwhile, AKIP1 overexpression increased CD133+ cell rate and enhanced spheres formation efficiency in 22Rv1 and LNCaP cells. Reversely, AKIP1 knockdown exhibited the opposite effect in 22Rv1 and LNCaP cells. Further RNA sequencing analysis exhibited that AKIP1-modified DEGs were enriched in the oncogenic signaling pathways related to prostate cancer, such as PI3K-Akt, MEK/ERK, mTOR signaling pathways. The following western blot indicated that AKIP1 overexpression activated while its knockdown blocked PI3K-Akt, MEK/ERK, mTOR signaling pathways in prostate cancer cells. Clinically, AKIP1 was upregulated in the prostate tumor tissues compared with paired adjacent tissues, and its tumor high expression correlated with increased pathological T, pathological N stage and poor prognosis in prostate cancer patients. Conclusion: AKIP1 promotes cell proliferation, invasion, stemness, activates PI3K-Akt, MEK/ERK, mTOR signaling pathways and correlates with worse tumor features and prognosis in prostate cancer.

Beetroot and leaf extracts present protective effects against prostate cancer cells, inhibiting cell proliferation, migration, and growth signaling pathways

2021 ◽  
Author(s):  
Mariana Camargo Silva Mancini ◽  
Luis Gustavo Saboia Ponte ◽  
Cayo Henrique Rocha Silva ◽  
Isabella Fagundes ◽  
Isadora Carolina Betim Pavan ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Signaling Pathways ◽  
Protective Effects ◽  
Prostate Cancer Cells ◽  
Leaf Extracts

scholarly journals Clinical Investigation and Biological Mechanism of Tigecycline on Coagulation Disorders in Cancer Patients

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 25-25
Author(s):  
Dawei Wang ◽  
Guoyan Wu ◽  
Xueping Li ◽  
Dejun Deng ◽  
Xiaopeng Tian ◽  
...  
Keyword(s):  
Prothrombin Time ◽  
Cancer Patients ◽  
Rna Sequencing ◽  
Platelet Activation ◽  
Cho Cells ◽  
Sequencing Analysis ◽  
Biological Mechanism ◽  
Coagulation Disorders ◽  
Blood Cancer ◽  
D Dimer

Tigecycline, a first representative of the new class of glycylcycline antibacterial drugs, has been approved by FDA for using in the treatment of complicated skin and skin structure infections and community-acquired pneumonia in adults in 2005. It has been widely used in hospitals due to its broad-spectrum activity against pathogens. Pre-clinical studies showed that tigecycline has a significant anti-bacterial effect with low and mild adverse drug reactions (ADRs), including nausea, vomit or some other ADRs. Accompany with the huge increase of tigecycline usage in China, more and more side effects began to arouse people's attention. Here, we found that tigecycline can cause coagulation abnormalities in cancer patients, especially with hematological malignance, through clinical observation and retrospective analysis. To analyze the effect and risk factors of tigecycline on coagulation index in severely infected patients with hematologic cancer, we screened the cases admitted to department of hematology from three hospitals treated with tigecycline from Nov, 2015 to Oct, 2019. Then we compared the differences among the prothrombin time (PT), prothrombin time activity (PT %), the international standardization ratio (INR), part of the activation of prothrombin time (APTT), fibrinogen (FBG), thrombin time (TT), D-Dimer, fibrin degradation products (FDP), platelet (PLT), alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (CRE), and c-reactive protein (CRP) before and after the tigecycline treatment. Meanwhile, we tend to establish the relationship between coagulation function and the time of tigecycline usage. In addition, for exploring the potential cause of abnormal coagulation induced by tigecycline, we evaluated the underlying biological mechanisms via Chinese hamster ovary (CHO) cells treated by tigecycline in vitro and subsequent RNA-sequencing analysis. A total of 129 qualified cases were included for analysis, including 71 males (55%) and 58 females (45%), with average age of 49.5±15.9 years old. After the treatment with tigecycline, PT, APTT and TT were significantly prolonged (P < 0.05). The INR, D-Dimer and FDP levels also increased (P < 0.05), but the FBG concentration was significantly reduced (P < 0.05) which indicated the possibility of hypofibrinogenaemia. Moreover, the coagulation parameters were tremendously changed in the early stage after intravenous infusion of tigecycline for anti-infection. There was no significant change in PLT count, but the levels of ALT, AST, CRE and CRP in the patients were statistically significant declined (P < 0.05). Most of all, the liver and kidney function of the patients was recovered after the infection was controlled by tigecycline treatment. In addition, the adhesion and stretching function of CHO cells were significantly suppressed after tigecycline treatmentin vitro. Lastly, bulk RNA-sequencing assay showed significant abnormalities in gene sets associated with platelet-activation and coagulation, such as PKFP, PLA2g7, PDGFRA, PDGFRB, PAFAH1b3, PDGFA, PECAM1, PDGFC and MPIG6b. Furthermore, adhesion regulating molecules RPN13, CHL1, ICAM5, TLCN were also downregulated by tigecycline treatment. What's more, these key genes which showed above need to be further validated in blood samples of AML patients when treated with tigecycline. Taken together, tigecycline can cause coagulation disorders in blood cancer patients. As we known, blood cancer could disturb the normal hematopoietic reconstitution in bone marrow, which resulted in abnormal numbers and functions of the peripheral blood lineages. Hence, these ADRs can accelerate the disease progression, cause severe bleeding and increase the risk of mortality in these patients. The biological mechanism study of this abnormality showed that tigecycline could inhibit platelet activation and the expression of adhesion regulators, which may increase the risk of bleeding and threaten the safety of patients. Therefore, the monitoring of coagulation index during tigecycline treatment should be adopted. Disclosures No relevant conflicts of interest to declare.

Knockdown of long noncoding RNA AC245100.4 inhibits the tumorigenesis of prostate cancer cells via the STAT3/NR4A3 axis

Epigenomics ◽  
2021 ◽  
Author(s):  
Chi Liu ◽  
Ping Lin ◽  
Jiabin Zhao ◽  
Hui Xie ◽  
Rou Li ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Rna Sequencing ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Transcriptional Repressor ◽  
Sequencing Analysis ◽  
Loss Of Function ◽  
Prostate Cancer Cells ◽  
Rna Immunoprecipitation

Aim: To explore the role and mechanism of long noncoding RNA AC245100.4 and NR4A3 in prostate cancer (PCa). Methods: RNA-sequencing analysis was used to detect the downstream genes of AC245100.4. A series of gain- and loss-of-function approaches were used to investigate the roles of AC245100.4 and NR4A3. RNA immunoprecipitation was performed to examine the interaction between AC245100.4 and STAT3. Results: AC245100.4 was significantly upregulated in PCa cells and tissues. Knockdown of AC21500.4 significantly inhibited the tumorigenesis of PCa cells. Mechanistically, AC245100.4 deregulated the transcription of NR4A3 via increasing p-STAT3, which acted as a transcriptional repressor of NR4A3. Conclusion: Knockdown of lncRNA AC245100.4 inhibits the tumorigenesis of PCa cells via the STAT3/ NR4A3 axis.

scholarly journals EPA and DHA Inhibit Myogenesis and Downregulate the Expression of Muscle-related Genes in C2C12 Myoblasts

Genes ◽  
2019 ◽  
Vol 10 (1) ◽  
pp. 64 ◽  
Author(s):  
Jing Zhang ◽  
Xin Xu ◽  
Yan Liu ◽  
Lin Zhang ◽  
Jack Odle ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Cell Proliferation ◽  
Cell Viability ◽  
Rna Sequencing ◽  
Cell Counting ◽  
Sequencing Analysis ◽  
C2c12 Myoblasts ◽  
Epa And Dha ◽  
Proliferation And Differentiation

This study was conducted to elucidate the biological effects of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on cell proliferation, differentiation and gene expression in C2C12 myoblasts. C2C12 were treated with various concentrations of EPA or DHA under proliferation and differentiation conditions. Cell viability was analyzed using cell counting kit-8 assays (CCK-8). The Edu assays were performed to analyze cell proliferation. To analyze cell differentiation, the expressions of myogenic marker genes were determined at the transcriptional and translational levels by qRT-PCR, immunoblotting and immunofluorescence. Global gene expression patterns were characterized using RNA-sequencing. Phosphorylation levels of ERK and Akt were examined by immunoblotting. Cell viability and proliferation was significantly inhibited after incubation with EPA (50 and 100 μM) or DHA (100 μM). Both EPA and DHA suppressed C2C12 myoblasts differentiation. RNA-sequencing analysis revealed that some muscle-related genes were significantly downregulated following EPA or DHA (50 μM) treatment, including insulin-like growth factor 2 (IGF-2), troponin T3 (Tnnt3), myoglobin (Mb), myosin light chain phosphorylatable fast skeletal muscle (Mylpf) and myosin heavy polypeptide 3 (Myh3). IGF-2 was crucial for the growth and differentiation of skeletal muscle and could activate the PI3K/Akt and the MAPK/ERK cascade. We found that EPA and DHA (50 μM) decreased the phosphorylation levels of ERK1/2 and Akt in C2C12 myoblasts. Thus, this study suggested that EPA and DHA exerted an inhibitory effect on myoblast proliferation and differentiation and downregulated muscle-related genes expression.

scholarly journals Expression and Function of Lysophosphatidic Acid LPA1 Receptor in Prostate Cancer Cells

Endocrinology ◽  
2006 ◽  
Vol 147 (10) ◽  
pp. 4883-4892 ◽  
Author(s):  
Rishu Guo ◽  
Elizabeth A. Kasbohm ◽  
Puneeta Arora ◽  
Christopher J. Sample ◽  
Babak Baban ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Proliferation ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Lysophosphatidic Acid ◽  
Cell Cycle Progression ◽  
Receptor Activation ◽  
Lncap Cells ◽  
Prostate Cancer Cells ◽  
And Migration

The bioactive phospholipid lysophosphatidic acid (LPA) promotes cell proliferation, survival, and migration by acting on cognate G protein-coupled receptors named LPA1, LPA2, and LPA3. We profiled gene expression of LPA receptors in androgen-dependent and androgen-insensitive prostate cancer cells and found that LPA1 gene is differentially expressed in androgen-insensitive and LPA-responsive but not androgen-dependent and LPA-resistant cells. In human prostate specimens, expression of LPA1 gene was significantly higher in the cancer compared with the benign tissues. The androgen-dependent LNCaP cells do not express LPA1 and do not proliferate in response to LPA stimulation, implying LPA1 transduces cell growth signals. Accordingly, stable expression of LPA1 in LNCaP cells rendered them responsive to LPA-induced cell proliferation and decreased their doubling time in serum. Implantation of LNCaP-LPA1 cells resulted in increased rate of tumor growth in animals compared with those tumors that developed from the wild-type cells. Growth of LNCaP cells depends on androgen receptor activation, and we show that LPA1 transduces Gαi-dependent signals to promote nuclear localization of androgen receptor and cell proliferation. In addition, treatment with bicalutamide inhibited LPA-induced cell cycle progression and proliferation of LNCaP-LPA1 cells. These results suggest the possible utility of LPA1 as a drug target to interfere with progression of prostate cancer.

Role of GADD45α as a potential therapeutic target for prostate cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 10566-10566
Author(s):  
R. Singal ◽  
K. Ramachandran ◽  
G. Gopisetty ◽  
L. Navarro ◽  
E. Gordian ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Proliferation ◽  
Cancer Cells ◽  
Therapeutic Target ◽  
Recombinant Expression ◽  
Proximal Promoter ◽  
Lncap Cells ◽  
Potential Therapeutic Target ◽  
Du145 Cells ◽  
Docetaxel Chemotherapy

10566 Background: Defects in the apoptotic pathway contribute to uncontrolled cell proliferation of cancer cells and confer resistance to chemotherapeutic drugs. Understanding the mechanisms of deregulation of apoptosis related genes would enable targeted treatment methods to improve the efficacy of chemotherapy. Growth Arrest and DNA Damage inducible, alpha (GADD45a) mediates cytotoxicity of docetaxel chemotherapy. We examined the mechanism of regulation of GADD45a in prostate cancer cells and the effect of its upregulation on sensitivity to docetaxel chemotherapy. Methods: Levels of GADD45a in Du145, LNCaP and PC3 were analyzed by real time reverse transcriptase PCR and western blotting. DNA methylation was studied by bisulfite sequencing. Chromatin immunoprecipitation was used to study interaction of methyl binding proteins to GADD45 5’ sequence. Cytotoxicity after drug treatment was measured by MTT cell proliferation assay. Apoptosis assays were done by Annexin V/propidium iodide staining followed by flow cytometry. Results: Levels of expression of GADD45a in Du145 and LNCaP cells were lower than that in PC3. A 4 CpG region upstream of the proximal promoter region was methylated in Du145 and LNCaP cells. Methylation was reversed by treatment of Du145 and LNCaP cells with DNA methyl transferase (DNMT) inhibitors such as 5- Azacytidine or 5- Aza deoxycytidine leading to reactivation of GADD45a expression in these cells. This region was also frequently methylated in prostate cancer tissues. Methyl binding protein, MeCP2 was associated with the methylated 4 CpGs in Du145 and knock down of MeCP2 by transfection of MeCP2 siRNA vector in Du145 cells (Du145-MeCP2-ve) led to increased expression of GADD45a, without affecting the methylation status of the gene. Enhanced sensitivity to docetaxel was observed by upregulation of GADD45a in Du145 cells by (a) recombinant expression of GADD45a (b) downregulation of MeCP2 and (c) pretreatment with 5-Azacytidine. Conclusions: GADD45a is frequently deregulated in prostate cancer by methylation of 5’ 4 CpG region and is a potential therapeutic target for treatment of prostate cancer. [Table: see text]

Tumor-normal sequencing to reveal frequency of false positive error rates with tumor-only sequencing in GI cancers and with RNA sequencing as a new standard of precision molecular profiling.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 224-224
Author(s):  
Chad Garner ◽  
Sandip Reddy ◽  
John Z Sanborn ◽  
Stephen Charles Benz ◽  
Patrick Soon-Shiong ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Rna Sequencing ◽  
False Positive ◽  
False Positive Rate ◽  
Molecular Targets ◽  
Sequencing Analysis ◽  
Rna Analysis ◽  
Gi Cancer ◽  
Positive Rate ◽  
Tumor Genome

224 Background: Tumor-only sequencing to identify somatic tumor genomic variants increases the risk of mistakenly identifying germline mutations as somatically derived driver mutations. Simultaneous bioinformatics analysis of both normal germline and the tumor genome with RNA analysis is necessary for precise identification of molecular targets for cancer therapy. The objective of this study was to compare the accuracy and precision of tumor somatic SNV calling with a 45-gene GI cancer molecular actionability panel, analyzing tumor tissue alone versus analyzing tumor DNA with normal germline DNA and tumor RNA. Methods: The study included 204 cancer patients with 11 GI cancer types with whole genome sequencing of tumor and normal genomes. True positive and false positive rates were measured for single nucleotide variants (SNVs). RNA sequencing was available for 139 patients to determine SNVs expressed in messenger RNA. SNVs were identified using well-established and published bioinformatics methods. False positive results were SNVs identified as being somatic origin that were of germline origin. Results: 92% SNVs identified from sequencing tumor genomes alone were of germline origin (false positives) rather than true somatic mutations. Filtering the SNVs using a public database with reported population allele frequencies < 0.001 still resulted in a false positive rate of 41%. Furthermore, 71% of GI cancer patients had at least one false positive SNV after filtering. RNA analysis showed 10% of true somatic variants were not expressed and 17% of patients had at least one true somatic variant that was not expressed. Conclusions: Simultaneous sequencing and analysis of both normal germline and tumor genomes is necessary for accurate identification of molecular targets. Analysis of tumor genome alone results in a high false positive rate. Higher precision is achieved with simultaneous tumor-normal DNA and RNA sequencing analysis. Treatment decisions based on tumor-only DNA analysis or in the absence of RNA analysis can result in administration of ineffective therapies and increasing risk of negative drug-related side effects.

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