PTEN‐mediated G1 cell‐cycle arrest in LNCaP prostate cancer cells is associated with altered expression of cell‐cycle regulators

Duijn, Petra W van; Made, Angelique C. J. Ziel-van der; Korput, J.A.G. van der; Trapman, Jan

doi:10.1002/pros.21045

Cited by 30 publications

(17 citation statements)

References 46 publications

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“…The normalized PTEN DNA copy number change on chromosome 10 corresponding to the PTEN gene is consistent with the known PTEN status in these cell lines: null in PC3 and reduced in heterozygous LNCaP cells but 2 copies in VCaP cells [43–45] (Fig 4H). Based on our CNV cutoff (Z score > 3 for amplification, or < -3 for loss), 1/8 LNCaP, 6/7 PC3, and 0/5 VCaP cells were called as PTEN loss.…”

Section: Resultssupporting

confidence: 77%

Chromosomal Instability Estimation Based on Next Generation Sequencing and Single Cell Genome Wide Copy Number Variation Analysis

et al. 2016

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Genomic instability is a hallmark of cancer often associated with poor patient outcome and resistance to targeted therapy. Assessment of genomic instability in bulk tumor or biopsy can be complicated due to sample availability, surrounding tissue contamination, or tumor heterogeneity. The Epic Sciences circulating tumor cell (CTC) platform utilizes a non-enrichment based approach for the detection and characterization of rare tumor cells in clinical blood samples. Genomic profiling of individual CTCs could provide a portrait of cancer heterogeneity, identify clonal and sub-clonal drivers, and monitor disease progression. To that end, we developed a single cell Copy Number Variation (CNV) Assay to evaluate genomic instability and CNVs in patient CTCs. For proof of concept, prostate cancer cell lines, LNCaP, PC3 and VCaP, were spiked into healthy donor blood to create mock patient-like samples for downstream single cell genomic analysis. In addition, samples from seven metastatic castration resistant prostate cancer (mCRPC) patients were included to evaluate clinical feasibility. CTCs were enumerated and characterized using the Epic Sciences CTC Platform. Identified single CTCs were recovered, whole genome amplified, and sequenced using an Illumina NextSeq 500. CTCs were then analyzed for genome-wide copy number variations, followed by genomic instability analyses. Large-scale state transitions (LSTs) were measured as surrogates of genomic instability. Genomic instability scores were determined reproducibly for LNCaP, PC3, and VCaP, and were higher than white blood cell (WBC) controls from healthy donors. A wide range of LST scores were observed within and among the seven mCRPC patient samples. On the gene level, loss of the PTEN tumor suppressor was observed in PC3 and 5/7 (71%) patients. Amplification of the androgen receptor (AR) gene was observed in VCaP cells and 5/7 (71%) mCRPC patients. Using an in silico down-sampling approach, we determined that DNA copy number and genomic instability can be detected with as few as 350K sequencing reads. The data shown here demonstrate the feasibility of detecting genomic instabilities at the single cell level using the Epic Sciences CTC Platform. Understanding CTC heterogeneity has great potential for patient stratification prior to treatment with targeted therapies and for monitoring disease evolution during treatment.

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Section: Resultssupporting

confidence: 77%

Chromosomal Instability Estimation Based on Next Generation Sequencing and Single Cell Genome Wide Copy Number Variation Analysis

et al. 2016

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“…However, our data here showed that the high expression of hepaCAM caused a G1 accumulation. Such a phenomenon has also been observed in other tumor suppressors such as PTEN, which arrested prostatic cancer cell cycle at G1 phase [Van Duijn et al, 2010], arrested melanoma at G2 phase [Jacob et al, 2009] and had no effect on the cell cycle of leukemia [Seminario et al, 2003]. These data suggested that hepaCAM may inhibit the proliferation of different cancer through different approaches.…”

Section: Discussionmentioning

confidence: 77%

HepaCAM induces G1 phase arrest and promotes c-Myc degradation in human renal cell carcinoma

Zhang

Luo

et al. 2011

J. Cell. Biochem.

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Hepatocyte cell adhesion molecule (hepaCAM) encodes a generally inactive phosphorylated glycoprotein which mediates cancer cell proliferation, migration, and differentiation. We have reported that hepaCAM is down-regulated in renal cell carcinoma (RCC) and takes responsibility of cell growth inhibition. However, the precise mechanisms of hepaCAM inhibits cell growth is still unknown. In this study, we demonstrated that re-expression of hepaCAM can cause an accumulation in G0/G1 phase in 786-0 cells. This reaction was accompanied by a substantial reduction of c-Myc expression through using an ectopic hepaCAM expression system. Furthermore, we found a comparable decrease in proliferation and G0/G1 accumulation of 786-0 and RC-2 cells after treatment with a small molecule c-Myc inhibitor, 10058-F4. This indicated that the down regulation of c-Myc was an essential process in controlling growth inhibitory actions of hepaCAM. Nevertheless, re-expression of hepaCAM results in apparent reduction of c-Myc protein with no corresponding reduction of c-Myc mRNA. This suggests that this reaction might take place at a post-transcriptional level rather than transcriptional one. Consistent with these findings, hepaCAM decreased c-Myc stability by increasing the proportion of c-Myc phosphorylation on T58 which can be abrogated by a proteasomal inhibitor (MG132). Thus, our research implies that the decrease in c-Myc protein expression, resulting from ectopic expression of hepaCAM, may contribute to the inhibition of proliferation in these cells.

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“…Increasing evidence supports anti-tumor roles for FOXO members in CaP. For instance, the loss of FOXO3a promotes cancer formation in the TRAMP CaP mouse model [24], whereas the upregulation or activation of FOXO proteins leads to growth arrest and apoptosis in CaP cells [25–27]. In contrast, Akt directly phosphorylates FOXO family members, thereby antagonizing the functions of FOXOs by promoting their association with 14-3-3 proteins and thus preventing their nuclear translocation [28].…”

Section: Discussionmentioning

confidence: 99%

GABARAPL1 suppresses metastasis by counteracting PI3K/Akt pathway in prostate cancer

Chen

et al. 2016

Oncotarget

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PTEN‐mediated G1 cell‐cycle arrest in LNCaP prostate cancer cells is associated with altered expression of cell‐cycle regulators

Abstract: The results indicate that PTEN dependent gene expression is important in cell-cycle regulation and is mediated by both Akt-dependent and -independent mechanisms.

Cited by 30 publications

References 46 publications

Chromosomal Instability Estimation Based on Next Generation Sequencing and Single Cell Genome Wide Copy Number Variation Analysis

Chromosomal Instability Estimation Based on Next Generation Sequencing and Single Cell Genome Wide Copy Number Variation Analysis

HepaCAM induces G1 phase arrest and promotes c-Myc degradation in human renal cell carcinoma

GABARAPL1 suppresses metastasis by counteracting PI3K/Akt pathway in prostate cancer

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