Human PinX1, a potent telomerase inhibitor, is not involved in human gastrointestinal tract carcinoma

Akiyama, Yuji; Maesawa, Chihaya; Wada, Kei; Fujisawa, Kentaro; Itabashi, Tetsuya; Noda, Yoshinori; Honda, Takehisa; Sato, Nobuhiro; Ishida, Kaoru; Takagane, Akinori; Saito, Kazuyoshi; Masuda, Tomoyuki

doi:10.3892/or.11.4.871

Cited by 11 publications

(16 citation statements)

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“…1B, the PinX1 protein was readily detectable in all tested cell types and without any signs of downregulation in transformed and cancerous cells as compared with the normal BJ cells. Other earlier studies had also indicated that the expression levels of PinX1 mRNA transcripts were not affected in multiple clinical cancers as compared with their corresponding normal tissues (15)(16)(17)(18). We suggest that PinX1 is ubiquitously expressed in human cells regardless of their telomerase activity or malignant status.…”

Section: Resultsmentioning

confidence: 57%

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Silencing PinX1 Compromises Telomere Length Maintenance As Well As Tumorigenicity in Telomerase-Positive Human Cancer Cells

et al. 2008

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The nucleolar protein PinX1 has been proposed to be a putative tumor suppressor due to its binding to and inhibition of the catalytic activity of telomerase, an enzyme that is highly expressed in most human cancers in which it counteracts telomere shortening-induced senescence to confer cancer cell immortalization. However, the role of PinX1 in telomere regulation, as well as in cancer, is still poorly understood. In this study, we showed that the PinX1 protein is constitutively expressed in various human cells regardless of their telomerase activity and malignant status. Most interestingly, we found that silencing PinX1 expression by a potent short hairpin RNA construct led to a robust telomere length shortening and growth inhibition in telomerase-positive but not in telomerase-negative human cancer cells. We further showed that silencing PinX1 significantly reduced the endogenous association of telomerase with the Pot1-containing telomeric protein complex, and therefore, could account for the phenotypic telomere shortening in the affected telomerasepositive cancer cells. Our results thus reveal a novel positive role for PinX1 in telomerase/telomere regulations and suggest that the constitutive expression of PinX1 attributes to telomere maintenance by telomerase and tumorigenicity in cancer cells. [Cancer Res 2009;69(1):75-83]

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Section: Resultsmentioning

confidence: 57%

“…Analyzing studies indicated that the expression of the PinX1 mRNA transcript is present in most tested human clinical tumors (15)(16)(17)(18). We also found that the PinX1 protein is constitutively expressed, without any signs of down-regulation, in multiple human cancer cell lines (Fig.…”

Section: Introductionmentioning

confidence: 58%

Silencing PinX1 Compromises Telomere Length Maintenance As Well As Tumorigenicity in Telomerase-Positive Human Cancer Cells

et al. 2008

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“…Although PinX1-TRF1 interaction has not been functionally characterized, the binding of PinX1 to TERT was experimentally shown to have a telomerase activity (TA)-inhibitory effect, suggesting that this protein might function as a cellular telomerase inhibitor. However, it is intriguing that the PinX1 expression appears not to be affected in most human cancer cells (Akiyama et al, 2004;Chang et al, 2004;Hawkins et al, 2004). We recently found that depletion of the PinX1 expression has an effect in suppressing telomerase association with the Pot1-containing telomeric protein complex, and it significantly shortens telomere lengths in telomerase-positive cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Anthracyclines disrupt telomere maintenance by telomerase through inducing PinX1 ubiquitination and degradation

Zhang

Dong

H.³

et al. 2011

Oncogene

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Telomere maintenance is essential for cancer growth. Induction of telomere dysfunction, for example, by inhibition of telomeric proteins or telomerase, has been shown to strongly enhance cancer cells' sensitivity to chemotherapies. However, it is not clear whether modulations of telomere maintenance constitute cancer cellular responses to chemotherapies. Furthermore, the manner in which anti-cancer drugs affect telomere function remains unknown. In this study, we show that anthracyclines, a class of anti-cancer drugs widely used in clinical cancer treatments, have an active role in triggering telomere dysfunction specifically in telomerase-positive cancer cells. Anthracyclines interrupt telomere maintenance by telomerase through the downregulation of PinX1, a protein factor responsible for targeting telomerase onto telomeres, thereby inhibiting telomerase association with telomeres. We further demonstrate that anthracyclines downregulate PinX1 by inducing this protein degradation through the ubiquitin-proteasome-dependent pathway. Our data not only reveal a novel action for anthracyclines as telomerase functional inhibitors but also provide a clue for the development of novel anti-cancer drugs based on telomerase/telomere targeting, which is actively investigated by many current studies.

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“…Pin 2/TRF 1 interacting protein 1 (PinX1) has been demonstrated to be a potential endogenous telomerase inhibitor that is able to inhibit the telomerase activity of some cancer cells' , resulting in apoptosis (5,6). However, this remains controversial as other studies have reported opposite findings (7,8). PinX1 may function via different mechanisms in different tumors, and the mechanisms underlying the inhibition of the telomerase or RNA are complex.…”

Section: Introductionmentioning

confidence: 79%

“…However, Sun et al (13) discovered that during the differentiation of emergent acute promyelocytic leukemia, the expression of PinX1mRNA was accordant with the telomerase activity, therefore it was concluded that the expression of PinX1 was just a reaction following the expression of hTERT, aimed at maintaining stable telomerase activity. Another hypothesis proposed that in prostatic carcinoma (14), gastrointestinal carcinoma (15) and medulloblastoma (16), the expression of PinX1 had no association with telomerase activity and was not the key inhibiting factor on telomerase activity, rather just (18) have demonstrated that, during the mitotic period, nucleolin aided the transport of PinX1 around the chromosome and enhanced the composition of the middle plate. All these studies suggested that PinX1 functions differently in various types of cancer and thus has different regulations and mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Biological significance of PinX1 telomerase inhibitor in esophageal carcinoma treatment

Fan

Yan²,

Geng

et al. 2016

Experimental and Therapeutic Medicine

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Abstract. In the present study, to investigate the expression of PinX1 gene and its functional effects in human esophageal carcinoma (Eca)-109 cell line, expression vectors of human PinX1 (pEGFP-C3-PinX1) and its small interfering RNA (PinX1-FAM-siRNA) were constructed and transfected into Eca-109 cells using Lipofectamine 2000. Firstly, the mRNA expression level of PinX1 was examined using reverse transcription-polymerase chain reaction (RT-PCR). Once successful transfection was achieved, the effects on the mRNA level of human telomerase reverse transcriptase (hTERT), telomerase activity, cell proliferation and apoptosis were examined by semi-quantitative RT-PCR, stretch PCR, MTT assay and flow cytometry, respectively. Analysis of restriction and sequencing demonstrated that the recombining plasmids were successfully constructed. The results also indicated that transfection with pEGFP-C3-PinX1 and PinX1-FAM-siRNA into Eca-109 cells significantly increased PinX1 mRNA, decreased hTERT mRNA by 29.9% (P<0.05), and significantly reduced telomerase activity (P<0.05), inhibited cell growth, and increased the cell apoptotic index from 19.27±0.76 to 49.73±2%. The transfected PinX1-FAM-SiRNA exhibited PinX1 mRNA expression levels that were significantly decreased by 70% (P<0.05), whereas the remaining characteristics of Eca-109 cells, including cell growth, mRNA level of hTERT, telomerase activity and cell apoptotic index were not altered. Exogenous PinX1 has been demonstrated to be highly expressed in human Eca. PinX1 can inhibit human telomerase activity and the expression of hTERT mRNA, reduce tumor cell growth and induce apoptosis. Notably, these inhibitory functions were inhibited by silencing PinX1 in Eca with PinX1-FAM-siRNA. PinX1 was successfully increased and decreased in the present study, demonstrating that it may be a potential telomerase activity inhibitor. As PinX1 is an endogenous telomerase inhibitor, it may be used as a novel tumor-targeted gene therapy.

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Human PinX1, a potent telomerase inhibitor, is not involved in human gastrointestinal tract carcinoma

Cited by 11 publications

References 0 publications

Silencing PinX1 Compromises Telomere Length Maintenance As Well As Tumorigenicity in Telomerase-Positive Human Cancer Cells

Silencing PinX1 Compromises Telomere Length Maintenance As Well As Tumorigenicity in Telomerase-Positive Human Cancer Cells

Anthracyclines disrupt telomere maintenance by telomerase through inducing PinX1 ubiquitination and degradation

Biological significance of PinX1 telomerase inhibitor in esophageal carcinoma treatment

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