Growth inhibitory effect on glioma cells of adenovirus-mediated p16/INK4a gene transfer in vitro and in vivo.

Lee, Seung Hwan; Kim, M. S.; Kwon, Hyunja; Park, I. C.; Park, M. J.; Lee, Choon Taek; Kim, Y. W.; Kim, C. M.; Hong, Siqi

doi:10.3892/ijmm.6.5.559

Cited by 16 publications

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“…The U87MG cell line is derived from a patient diagnosed with GBM and has inactivated PTEN 33 and INK4a/ARF 34, 35 but does not have amplified or mutated EGFR 6, 9. The introduction of ΔEGFR in U87MG cells (ΔEGFR‐U87MG) enhances their growth in vitro and in tumour xenografts in vivo 6, 9, 13.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of phosphatidylinositol 3‐kinase signaling negates the growth advantage imparted by a mutant epidermal growth factor receptor on human glioblastoma cells

Klingler‐Hoffmann

Bukczynska

Tiganis

2003

Intl Journal of Cancer

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In de novo glioblastoma multiforme, loss of the tumour suppressor protein PTEN can coincide with the expression of a naturally occurring mutant epidermal growth factor receptor known as ⌬EGFR. ⌬EGFR signals constitutively via the phosphatidylinositol 3-kinase (PI3K)/protein kinase Akt and mitogen-activated protein kinase pathways. In human U87MG glioblastoma cells that lack PTEN, ⌬EGFR expression enhances tumourigenicity by increasing cellular proliferation. Inhibition of PI3K signaling with the pharmacologic inhibitor wortmannin, or by the reconstitution of physiological levels of PTEN to dephosphorylate the lipid products of PI3K, negated the growth advantage imparted by ⌬EGFR on U87MG cells. PTEN reconstitution suppressed the elevated PI3K signaling, without affecting mitogen-activated protein kinase signaling and caused a delay in G1 cell cycle progression that was concomitant with increased cyclin-dependent protein kinase inhibitor p21CIP1/WAF1 protein levels. Our study provides insight into the mechanism by which ⌬EGFR may contribute to glioblastoma development. Key words: PTEN; ⌬EGFR; PI3KGlioblastoma multiforme (GBM) is the most aggressive, invasive and neurologically destructive of all primary brain tumours with 50% of patients dying within the first year of diagnosis. The epidermal growth factor receptor (EGFR) is a tyrosine kinase that is overexpressed or mutated in approximately half of all GBMs that develop de novo. 1 ⌬EGFR (also referred to as EGFRvIII and de2-7EGFR) is the most common of the EGFR mutants 1-5 and dimerises to autophosphorylate in the absence of ligand and signal constitutively to promote glioblastoma growth. 4 -7 Although constitutive, ⌬EGFR activation is considerably lower than that observed for the ligand-induced wild type EGFR. 8,9 As such, the signaling pathways activated, the mode of activation and indeed the consequence of activation may differ for ⌬EGFR. 10,11 Consistent with this we have shown recently that although the protein tyrosine phosphatase TCPTP can dephosphorylate both wild type EGFR and ⌬EGFR, it has no effect of EGFR-mediated extracellular signal-regulated kinase (ERK) 1/2 activation but suppresses ⌬EGFR-induced ERK1/2. 12 Elucidating the role of ⌬EGFR-induced signaling pathways in the context of tumour cells that harbour the genetic alterations that can coexist with ⌬EGFR, may provide novel insight into how ⌬EGFR enhances tumourigenicity.Previous studies have shown that the introduction of ⌬EGFR in U87MG glioblastoma cells, that do not have amplified or mutated EGFR, can enhance significantly the growth of tumour xenografts in nude mice 6,9,13 and that this enhanced tumorigenicity correlates with enhanced cellular proliferation and reduced apoptosis. 14 In vitro, the ⌬EGFR-mediated growth advantage on U87MG glioblastoma cells occurs when the cells are cultured in the absence of serum. 13,14 Prigent et al. 13 showed that ⌬EGFR expression in U87MG cells enhances GTP-Ras loading and that this is necessary for cellular proliferation. More recently, we showed that ...

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Section: Resultsmentioning

confidence: 99%

Inhibition of phosphatidylinositol 3‐kinase signaling negates the growth advantage imparted by a mutant epidermal growth factor receptor on human glioblastoma cells

Klingler‐Hoffmann

Bukczynska

Tiganis

2003

Intl Journal of Cancer

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“…In contrast, the control cells formed large tumors that were highly vascularized and had a necrotic center typical of glioma. Note that relatively few examples of retro virus-mediated transfer of the p16 cDNA in animal models of glioma are reported in the literature [29], although using a different cell line and several reports demonstrate the adeno viral transfer of p16 [30-32]. The C6/Wistar rat model continues to be widely used [33,34] and this study adds a new component to this system: retrovirus-mediated transfer followed by assessment of p1 6 function in tissue culture and in vivo.…”

Section: Discussionmentioning

confidence: 99%

Retroviral transfer of the p16INK4a cDNA inhibits C6 glioma formation in Wistar rats

et al. 2002

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BackgroundThe p16INK4A gene product halts cell proliferation by preventing phosphorylation of the Rb protein. The p16INK4a gene is often deleted in human glioblastoma multiforme, contributing to unchecked Rb phosphorylation and rapid cell division. We show here that transduction of the human p16INK4a cDNA using the pCL retroviral system is an efficient means of stopping the proliferation of the rat-derrived glioma cell line, C6, both in tissue culture and in an animal model. C6 cells were transduced with pCL retrovirus encoding the p16INK4a, p53, or Rb genes. These cells were analyzed by a colony formation assay. Expression of p16INK4a was confirmed by immunohistochemistry and Western blot analysis. The altered morphology of the p16-expressing cells was further characterized by the senescence-associated β-galactosidase assay. C6 cells infected ex vivo were implanted by stereotaxic injection in order to assess tumor formation.ResultsThe p16INK4a gene arrested C6 cells more efficiently than either p53 or Rb. Continued studies with the p16INK4a gene revealed that a large portion of infected cells expressed the p16INK4a protein and the morphology of these cells was altered. The enlarged, flat, and bi-polar shape indicated a senescence-like state, confirmed by the senescence-associated β-galactosidase assay. The animal model revealed that cells infected with the pCLp16 virus did not form tumors.ConclusionOur results show that retrovirus mediated transfer of p16INK4a halts glioma formation in a rat model. These results corroborate the idea that retrovirus-mediated transfer of the p16INK4a gene may be an effective means to arrest human glioma and glioblastoma.

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“…Such experiments demonstrated the proof of concept with promising efficacy in reducing tumor cell proliferation and prolonging the lifespan of the treated animals (98). In glioblastoma, the most malignant form of glioma, RB is inactivated in at least 30% of tumors and greater than 50% have disrupted RB pathway including homozygous p16 INK4 gene deletions (99). Alternative therapies are also highly desirable in glioblastoma as the existence of the blood-brain barrier renders strong resistance to most anticancer therapeutic agents due to low permeability across the barrier.…”

Section: Gene Therapymentioning

confidence: 99%

Targeting Tumor Suppressor Networks for Cancer Therapeutics

Guo¹,

Ngo²,

Modrek³

et al. 2014

CDT

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Cancer is a consequence of mutations in genes that control cell proliferation, differentiation and cellular homeostasis. These genes are classified into two categories: oncogenes and tumor suppressor genes. Together, overexpression of oncogenes and loss of tumor suppressors are the dominant driving forces for tumorigenesis. Hence, targeting oncogenes and tumor suppressors hold tremendous therapeutic potential for cancer treatment. In the last decade, the predominant cancer drug discovery strategy has relied on a traditional reductionist approach of dissecting molecular signaling pathways and designing inhibitors for the selected oncogenic targets. Remarkable therapies have been developed using this approach; however, targeting oncogenes is only part of the picture. Our understanding of the importance of tumor suppressors in preventing tumorigenesis has also advanced significantly and provides a new therapeutic window of opportunity. Given that tumor suppressors are frequently mutated, deleted, or silenced with loss-of-function, restoring their normal functions to treat cancer holds tremendous therapeutic potential. With the rapid expansion in our knowledge on cancer over the last several decades, developing effective anticancer regimens against tumor suppressor pathways has never been more promising. In this article, we will review the concept of tumor suppression, and outline the major therapeutic strategies and challenges of targeting tumor suppressor networks for cancer therapeutics.

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Growth inhibitory effect on glioma cells of adenovirus-mediated p16/INK4a gene transfer in vitro and in vivo.

Cited by 16 publications

References 0 publications

Inhibition of phosphatidylinositol 3‐kinase signaling negates the growth advantage imparted by a mutant epidermal growth factor receptor on human glioblastoma cells

Inhibition of phosphatidylinositol 3‐kinase signaling negates the growth advantage imparted by a mutant epidermal growth factor receptor on human glioblastoma cells

Retroviral transfer of the p16INK4a cDNA inhibits C6 glioma formation in Wistar rats

Targeting Tumor Suppressor Networks for Cancer Therapeutics

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