Deregulation Of PTEN Research Articles

PTEN Deregulation Mechanisms in Salivary Gland Carcinomas.

Among the tumour suppressor genes that affect critically cell functions and homeostasis, phosphatase and tensin homolog deleted in chromosome 10 (PTEN- gene locus: 10q21) regulates the PI3K/Akt/mTOR signalling pathway. PTEN is deleted, mutated or epigenetically hyper-methylated in a variety of human solid malignancies. Salivary gland carcinomas (SGCs) belong to the head and neck carcinomas (HNCs) super category of solid malignancies. Histo-pathologically, they demonstrate a significant diversity due to a variety of distinct and mixed subtypes. Genetically, they are characterized by a broad spectrum of gene and chromosomal imbalances. Referring specifically to suppressor genes, PTEN deregulation plays a critical role in signaling transduction in the corresponding SGC pre- and malignant epithelia modifying the response rates to potential targeted therapeutic strategies. In the current review, we explored the role of PTEN deregulation mechanisms that are involved in the onset and progression of SGCs.

Pten knockout affects drug resistance differently in melanoma and kidney cancer

BackgroundPTEN is a tumor suppressor that is often mutated and nonfunctional in many types of cancer. The high heterogeneity of PTEN function between tumor types makes new Pten knockout models necessary to assess its impact on cancer progression and/or treatment outcomes.MethodsWe aimed to show the effect of CRISPR/Cas9-mediated Pten knockout on murine melanoma (B16 F10) and kidney cancer (Renca) cells. We evaluated the effect of PTEN deregulation on tumor progression in vivo and in vitro, as well as on the effectiveness of drug treatment in vitro. In addition, we studied the molecular changes induced by Pten knockout.ResultsIn both models, Pten mutation did not cause significant changes in cell proliferation in vitro or in vivo. Cells with Pten knockout differed in sensitivity to cisplatin treatment: in B16 F10 cells, the lack of PTEN induced sensitivity and, in Renca cells, resistance to drug treatment. Accumulation of pAKT was observed in both cell lines, but only Renca cells showed upregulation of the p53 level after Pten knockout. PTEN deregulation also varied in the way that it altered PAI-1 secretion in the tested models, showing a decrease in PAI-1 in B16 F10 Pten/KO and an increase in Renca Pten/KO cells. In kidney cancer cells, Pten knockout caused changes in epithelial to mesenchymal transition marker expression, with downregulation of E-cadherin and upregulation of Snail, Mmp9, and Acta2 (α-SMA).ConclusionsThe results confirmed heterogenous cell responses to PTEN loss, which may lead to a better understanding of the role of PTEN in particular types of tumors and points to PTEN as a therapeutic target for personalized medicine.

Long-term treatment of cancer-prone germline PTEN mutant micewith low-dose rapamycin extends lifespan and delays tumour development.

PTEN is one of the most commonly inactivated tumour suppressor genes in sporadic cancer. Germline heterozygous PTEN gene alterations also underlie PTEN hamartoma tumour syndrome (PHTS), a rare human cancer-predisposition condition. A key feature of systemic PTEN deregulation is the inability to adequately dampen PI3-kinase (PI3K)/mTORC1 signalling. PI3K/mTORC1 pathway inhibitors such as rapamycin are therefore expected to neutralise the impact of PTEN loss, rendering this a more druggable context compared with those of other tumour suppressor pathways such as loss of TP53. However, this has not been explored in cancer prevention in a model of germline cancer predisposition, such as PHTS. Clinical trials of short-term treatment with rapamycin have recently been initiated for PHTS, focusing on cognition and colon polyposis. Here, we administered a low dose of rapamycin from the age of 6 weeks onwards to mice with heterozygous germline Pten loss, a mouse model that recapitulates most characteristics of human PHTS. Rapamycin was well tolerated and led to a highly significant improvement of survival in both male and female mice. This was accompanied by a delay in, but not full blockade of, the development of a range of proliferative lesions, including gastro-intestinal and thyroid tumours and endometrial hyperplasia, with no impact on mammary and prostate tumours, and no effect on brain overgrowth. Our data indicate that rapamycin may have cancer prevention potential in human PHTS. This might also be the case for sporadic cancers in which genetic PI3K pathway activation is an early event in tumour development, such as endometrial cancer and some breast cancers. To the best of our knowledge, this is the first report of a long-term treatment of a germline cancer predisposition model with a PI3K/mTOR pathway inhibitor. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Protein phosphatase Mg2+ /Mn2+ dependent-1A and PTEN deregulation in renal fibrosis: Novel mechanisms and co-dependency of expression.

PPM1A and PTEN emerged as novel suppressors of chronic kidney disease (CKD). Since loss of PPM1A and PTEN in the tubulointerstitium promotes fibrogenesis, defining molecular events underlying PPM1A/PTEN deregulation is necessary to develop expression rescue as novel therapeutic strategies. Here we identify TGF-β1 as a principle repressor of PPM1A, as conditional renal tubular-specific induction of TGF-β1 in mice dramatically downregulates kidney PPM1A expression. TGF-β1 similarly attenuates PPM1A and PTEN expression in human renal epithelial cells and fibroblasts, via a protein degradation mechanism by promoting their ubiquitination. A proteasome inhibitor MG132 rescues PPM1A and PTEN expression, even in the presence of TGF-β1, along with decreased fibrogenesis. Restoration of PPM1A or PTEN similarly limits SMAD3 phosphorylation and the activation of TGF-β1-induced fibrotic genes. Concurrent loss of PPM1A and PTEN levels in aristolochic acid nephropathy further suggests crosstalk between these repressors. PPM1A silencing in renal fibroblasts, moreover, results in PTEN loss, while PTEN stable depletion decreases PPM1A expression with acquisition of a fibroproliferative phenotype in each case. Transient PPM1A expression, conversely, elevates cellular PTEN levels while lentiviral PTEN introduction increases PPM1A expression. PPM1A and PTEN, therefore, co-regulate each other's relative abundance, identifying a previously unknown pathological link between TGF-β1 repressors, contributing to CKD.

PTEN and Gynecological Cancers.

PTEN is a tumour suppressor gene, and its loss of function is frequently observed in both heritable and sporadic cancers. It is involved in a great variety of biological processes, including maintenance of genomic stability, cell survival, migration, proliferation and metabolism. A better understanding of PTEN activity and regulation has therefore emerged as a subject of primary interest in cancer research. Gynaecological cancers are variously interested by PTEN deregulation and many perspective in terms of additional prognostic information and new therapeutic approaches can be explored. Here, we present the most significant findings on PTEN in gynaecological cancers (ovarian, endometrial, cervical, vulvar and uterine cancer) focusing on PTEN alterations incidence, biological role and clinical implications.

Effects of microRNA-20a on the proliferation, migration and apoptosis of multiple myeloma via the PTEN/PI3K/AKT signaling pathway.

Multiple myeloma (MM) is a heterogeneous disease with a poor prognosis. Circulating microRNAs (miRNAs) have shown potential as non-invasive prognostic biomarkers for heterogeneous diseases. miR-20a has been shown involved in various human cancers, and the phosphatase and tensin homolog/phosphoinositide 3-kinase/protein kinase B (PTEN/P13K/Akt) signaling pathway plays a key role in cell proliferation, migration and apoptosis. Here, we investigated the effect of miR-20a on the PTEN/PI3K/Akt signaling pathway during MM cell proliferation, migration and apoptosis. Reverse transcription quantitative polymerase chain reaction was applied to detect miR-20a expression in plasma from 30 MM patients and MM cell lines. CCK-8 assays, Transwell assays, Annexin V/PI double-staining and western blotting were performed to examine the protein expressions of PTEN, PI3K and Akt during cellullar proliferation, migration, cycling, and apoptosis. Significant upregulation of miR-20a and deregulation of PTEN were observed in MM cells. We also identified PTEN as a downstream target gene of miR-20a, which bound to the 3'-untranslated region of PTEN. Overexpression of miR-20a was associated with decreased PTEN expression, and treatment with miR-20a inhibitors decreased cell proliferation, migration and clonogenicity and reduced the protein expressions of PI3K and p-Akt but increased PTEN protein expression compared with blank and negative control groups. Taken together, these results showed that inhibition of miR-20a suppresses MM progression by modulating the PTEN/PI3K/Akt signaling pathway. These findings suggest that miR-20a may be a novel molecular therapeutic target for the treatment of MM.

Akt-p53-miR-365-cyclin D1/cdc25A axis contributes to gastric tumorigenesis induced by PTEN deficiency

Although PTEN/Akt signaling is frequently deregulated in human gastric cancers, the in vivo causal link between its dysregulation and gastric tumorigenesis has not been established. Here we show that inactivation of PTEN in mouse gastric epithelium initiates spontaneous carcinogenesis with complete penetrance by 2 months of age. Mechanistically, activation of Akt suppresses the abundance of p53, leading to decreased transcription of miR-365, thus causing upregulation of cyclin D1 and cdc25A, which promotes gastric cell proliferation. Importantly, genetic ablation of Akt1 restores miR-365 expression and effectively rescues gastric tumorigenesis in PTEN-mutant mice. Moreover, orthotopic restoration of miR-365 represses PTEN-deficient-induced hyperplasia. In human gastric cancer tissues, miR-365 reduction correlates with poorly differentiated histology, deep invasion and advanced stage, as well as the deregulation of PTEN, phosphorylated Akt, p53, cyclin D1 and cdc25A. These data demonstrate that the PTEN-Akt-p53-miR-365-cyclin D1/cdc25A axis serves as a new mechanism underlying gastric tumorigenesis, providing potential new therapeutic targets.

Abstract B05: The tumor suppressor gene pten regulates gene expression through histone H3.3 deposition and Daxx interaction

Abstract Sustaining proliferation is one of many capabilities acquired during tumor progression, where the PI3-kinase signaling pathway is a positive regulator of this trait and the tumor suppressor gene PTEN (phosphatase and tensin homology, deleted on chromosome ten) a negative regulator. Since PTEN deregulation is a central component of cancer progression, we decided to investigate how PTEN post-translational modifications modulate its function and protein interactions. We found that the histone chaperon protein Daxx (death domain-associated protein) associates with PTEN, in vivo and in vitro, and regulates PTEN stability through acetylation and ubiquitination. Moreover, we observed that PTEN regulates Histone 3.3 (H3.3 variant) deposition in the chromatin, by limiting Daxx interactions. We found an elevated H3.3-Daxx association in pten null cells, compared with pten-wt cells, correlating with a low H3.3 enrichment in the promoter of some driver tumor genes (Fos, Myc, Cyclin D1 and Bcl2) and an increased gene expression of them. We further demonstrated that this indirect gene expression regulation by PTEN is independent of its lipid-phosphatase activity. In conclusion, we hypothesize that PTEN may be mediating its tumor suppression function in part by regulating H3.3 deposition, and gene expression, through Daxx interaction. Citation Format: Jorge A. Benitez, Webster K. Cavenee, Frank B. Furnari. The tumor suppressor gene pten regulates gene expression through histone H3.3 deposition and Daxx interaction. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr B05.

The Role of Tumor Suppressor Dysregulation in Prostate Cancer Progression

Androgen receptor activity is essential for prostate cancer development and progression. While there are classically defined roles for the retinoblastoma (Rb) and p53 tumor suppressor pathways in maintenance of cell cycle control and the DNA damage response, recent studies have demonstrated a direct role of these two pathways in regulating AR expression and function. While the role of Pten deregulation in prostate cancer has provided much insight in to the mechanisms underlying prostate cancer initiation and progression, emerging roles for Rb and p53 are likely to further expand upon our understanding of tumor suppressor/nuclear receptor interaction. As disconnecting mitogenic signaling from AR-mediated gene transcription underlies the progression to castrate resistant prostate cancer (CRPC), functional inactivation of these two tumor suppressor pathways represents one mechanism through which AR protein levels can be upregulated and AR-mediated gene transcription can become aberrant. Importantly, recent advances in small molecule inhibitor design and discovery have led to the identification of agents capable of targeting these two prominent pathways and restoring the function of deregulated wild-type Rb and p53 protein. While such agents have undergone extensive study in many solid tumor types, the additional importance of Rb and p53 in restraining transcription of the AR gene within the prostate provides impetus for examining how loss of these two tumor suppressor proteins can facilitate transition of prostate cancers to CRPC. As will be reviewed in this article, restoration of Rb and p53 functions are not only important in regard to shortterm cell cycle regulation and response to genomic stresses, but likely have direct implications for deregulation of the AR locus.

720 Simultaneous HER2/neu and PTEN deregulation correlates with aggressive phenotype in hepatocellular carcinoma: a tissue microarray analysis

720 Simultaneous HER2/neu and PTEN deregulation correlates with aggressive phenotype in hepatocellular carcinoma: a tissue microarray analysis

Everolimus in combination with weekly paclitaxel and trastuzumab in patients (pts) with HER2-overexpressing metastatic breast cancer (MBC) with prior resistance to trastuzumab and taxanes: A multicenter phase II clinical trial.

1013^ Background: Resistance to trastuzumab (H) may be associated with deregulation of PTEN or mutations in PI3K/AKT pathway. Preclinically, everolimus (E), an oral inhibitor of mTOR, enhances activity, reverses resistance to H and demonstrates synergistic activity with paclitaxel (T). The objective of this phase II study was to evaluate the efficacy of E combined with T and H in heavily pretreated HER2-positive MBC pts. Methods: A multicenter, Novartis sponsored, phase II trial was conducted using: T 80mg/m2, IV on days 1, 8 and 15 q4w; H 4mg/kg IV loading dose, then weekly 2mg/kg; E daily 10mg in patients whose disease is resistant to both H (progression on or within 3 months of the end of H therapy for metastatic cancer or within 12 months after the end of neoadjuvant or adjuvant H) and taxanes (progression on or within 4 months of the end of taxane therapy for metastatic cancer or within 12 months after the end of neoadjuvant or adjuvant therapy.) Treatment continued until progression or unacceptable toxicity. Results: The study completed enrollment (n=55). Analyses were performed on 37 evaluable pts. Median treatment duration is 12 weeks (2-43) with19 pts still on treatment and 6 beyond 6 cycles. Pt characteristics were median age 56 y; visceral disease in 33 pts (89%) with lung and liver involvement in 18 pts (49%) and 21 pts (57%), respectively; median no. of prior chemo lines for metastatic disease 3 (range 0-8); prior anthracyclines in 25 pts (68%); prior lapatinib in 23 pts (62%). Twenty-five pts were evaluable for efficacy. We observed 5 (20%) confirmed PRs, 14 (56%) SDs and 6 (24%) PDs. Treatment was well tolerated. G3-4 neutropenia occurred in 12 pts (32%) with 1 case of febrile neutropenia, G3 stomatitis in 5 pts (13%) and G3 asthenia/fatigue in 2 pts (5%). Conclusions: These preliminary results confirm a previous phase I study showing that E in combination with T and H has an acceptable safety profile and promising anticancer activity in HER2-positive MBC pts pretreated with trastuzumab and taxanes. Updated safety, efficacy, and PFS results will be presented. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis, Pfizer Novartis Novartis, Pfizer Genentech, Novartis In compliance with the guidelines established by the ASCO Conflict of Interest Policy (J Clin Oncol. 2006 Jan 20;24[3]:519-521) and the Accreditation Council for Continuing Medical Education (ACCME), ASCO strives to promote balance, independence, objectivity, and scientific rigor through disclosure of financial and other interests, and identification and management of potential conflicts. According to the ASCO Conflict of Interest Policy, the following financial and other relationships must be disclosed: employment or leadership position, consultant or advisory role, stock ownership, honoraria, research funding, expert testimony, and other remuneration (J Clin Oncol. 2006 Jan 20;24[3]:520). The ASCO Conflict of Interest Policy disclosure requirements apply to all authors who submit abstracts to the Annual Meeting. For clinical trials that began accrual on or after April 29, 2004, ASCO's Policy places some restrictions on the financial relationships of principal investigators (J Clin Oncol. 2006 Jan 20;24[3]:521). If a principal investigator holds any restricted relationships, his or her abstract will be ineligible for placement in the 2010 Annual Meeting unless the ASCO Ethics Committee grants an exception. Among the circumstances that might justify an exception are that the principal investigator (1) is a widely acknowledged expert in a particular therapeutic area; (2) is the inventor of a unique technology or treatment being evaluated in the clinical trial; or (3) is involved in international clinical oncology research and has acted consistently with recognized international standards of ethics in the conduct of clinical research. NIH-sponsored trials are exempt from the Policy restrictions. Abstracts for which authors requested and have been granted an exception in accordance with ASCO's Policy are designated with a caret symbol (^) in the Annual Meeting Proceedings. For more information about the ASCO Conflict of Interest Policy and the exceptions process, please visit www.asco.org/conflictofinterest.

Infrequent hypermethylation of the PTEN gene in Korean non‐small‐cell lung cancers

CpG islands (CGIs) hypermethylation is implicated in the pathogenesis of many cancers, including lung cancer. The phosphate and tension homolog (PTEN) is a tumor suppressor that controls a variety of biological processes including cell proliferation, growth, migration, and death. The defects in PTEN regulation have a profound impact on carcinogenesis. Herein, we have examined the methylation status of the human PTEN gene in 137 primary non-small-cell lung cancers (NSCLCs) by using a methylation-specific PCR and correlated the results with clinicopathological features. Promoter methylation of the PTEN gene was observed in 5.1%, 2.9%, and 0.0% of three different CpG regions, which were localized at -1460 to -1263, -984 to -848, and -300 to -128 nucleotides upstream of the translation start site, respectively. Reverse transcription-PCR and immunohistochemical analysis showed the methylation of the CGI region at -984 to -848 correlated more accurately with PTEN expression. In addition, no significant correlation was found between PTEN methylation and clinicopathological factors, including the survival rates. These findings suggest that promoter methylation is not an important mechanism for PTEN deregulation in NSCLCs from Koreans.

Comparative genomic and functional analyses reveal a novel cis-acting PTEN regulatory element as a highly conserved functional E-box motif deleted in Cowden syndrome

Germline mutations in PTEN, encoding a phosphatase on 10q23, cause Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRRS). Approximately, 10% of CS-related PTEN mutations occur in the PTEN promoter and 11% of BRRS-related mutations include large deletions, often favoring the gene's 5' end (exon 1, promoter). In order to better understand the mechanism(s) underlying the deregulation of PTEN in these syndromes, it is important that functional cis-regulatory elements be identified. We employed a comparative genomic approach combined with molecular genetic techniques to identify a highly conserved sequence upstream of the PTEN promoter, sharing 80% sequence identity among Homo sapiens, Mus musculus and Rattus norvegicus. Within this region, we identified a canonical E-box sequence (CACGTG) located at position -2181 to -2176, approximately 800 bp upstream of the PTEN core promoter and more than 1.1 kb upstream of its minimal promoter region (located at -958 to -821). In vitro assays suggest that this motif is recognized by members of the basic region-helix-loop-helix-leucine-zipper (bHLH-LZ) transcription factor family, USF1 and USF2, and reporter assays indicate that this novel E-box is involved in mediating PTEN transcriptional activation. Four of 30 CS/CS-like patients, without previously identified PTEN mutations, were found with germline deletions of the E-box element. Of the four, three had deletions stretching to exon 1, but not 3' of it; importantly, one classic CS patient harbored a germline deletion localizing to this E-box region, further affirming the role of this element in PTEN's regulation and deregulation, and its contribution to the pathogenesis of CS.

PTEN, a negative regulator of PI3 kinase signalling, alters tau phosphorylation in cells by mechanisms independent of GSK-3

Deregulation of PTEN/Akt signalling has been recently implicated in the pathogenesis of Alzheimer’s disease (AD), but the effects on the molecular processes underlying AD pathology have not yet been fully described. Here we report that overexpression of PTEN reduces tau phosphorylation in CHO cells. This effect was abrogated by mutant PTEN constructs with either a catalytically inactive point mutation (C124S) or with only inactive lipid phosphatase activity (G129E), suggesting an indirect, lipid phosphatase-dependent process. The predominant effects of PTEN on tau appeared to be mediated by reducing ERK1/2 activity, but were independent of Akt, GSK-3, JNK and the tau phosphatases PP1 and PP2A. Our studies provide evidence for an effect of PTEN on the phosphorylation of tau in AD pathogenesis, and provide some insight into the mechanisms through which deregulation of PTEN may contribute towards the progression of tauopathy.