PI3K Blockade by Ad-PTEN Inhibits Invasion and Induces Apoptosis in Radial Growth Phase and Metastatic Melanoma Cells

Stewart, Alexis L.; Mhashilkar, Abner M.; Yang, Xiaohong; Ekmekçioğlu, Sühendan; Saito, Yuji; Sieger, Kerry; Schrock, Robert D.; Onishi, Eric; Swanson, Xin; Mumm, John B.; Zumstein, Lou; Watson, Graham J.; Snary, David; Roth, Jack A.; Grimm, Elizabeth A.; Ramesh, Rajagopal; Chada, Sunil

doi:10.1007/bf03402025

Cited by 75 publications

(70 citation statements)

References 37 publications

(49 reference statements)

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“…17,18,21,[35][36][37] Analysis for p27 expression in colorectal cancer cells after Ad-PTEN treatment demonstrated no change in expression levels (data not shown). In support of our findings is the recent report by Stewart et al, 38 who demonstrated enforced expression of PTEN-inhibited growth of melanoma cells that are wtPTEN. The discrepancy in the results is not clear.…”

Section: Discussionsupporting

confidence: 92%

“…38 Prior to start of the experiment, transduction efficiency for the cell lines to be used was determined using an adenoviral vector carrying the green fluorescent protein (Ad-GFP). Treatment of cells with Ad-GFP different viral particle number per cell (vp/cell) demonstrated that more than 80% of the cells were transduced at 5000 vp/cell (data not shown).…”

Section: Viral Production and Transduction Efficiencymentioning

confidence: 99%

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Adenovirus-mediated transfer of the PTEN gene inhibits human colorectal cancer growth in vitro and in vivo

et al. 2003

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The tumor-suppressor gene PTEN encodes a multifunctional phosphatase that is mutated in a variety of human cancers. PTEN inhibits the phosphatidylinositol 3-kinase pathway and downstream functions, including activation of Akt/protein kinase B (PKB), cell survival, and cell proliferation in tumor cells carrying mutant-or deletion-type PTEN. In such tumor cells, enforced expression of PTEN decreases cell proliferation through cell-cycle arrest at G1 phase accompanied, in some cases, by induction of apoptosis. More recently, the tumor-suppressive effect of PTEN has been reported in ovarian and thyroid tumors that are wild type for PTEN. In the present study, we examined the tumor-suppressive effect of PTEN in human colorectal cancer cells that are wild type for PTEN. Adenoviral-mediated transfer of PTEN (Ad-PTEN) suppressed cell growth and induced apoptosis significantly in colorectal cancer cells (DLD-1, HT29, and SW480) carrying wtPTEN than in normal colon fibroblast cells (CCD-18Co) carrying wtPTEN. This suppression was induced through downregulation of the Akt/PKB pathway, dephosphorylation of focal adhesion kinase (FAK) and mitogen-activated protein kinase (MAPK) and cell-cycle arrest at the G2/M phase, but not the G1 phase. Furthermore, treatment of human colorectal tumor xenografts (HT-29, and SW480) with Ad-PTEN resulted in significant (P¼0.01) suppression of tumor growth. These results indicate that Ad-PTEN exerts its tumorsuppressive effect on colorectal cancer cells through inhibition of cell-cycle progression and induction of cell death. Thus Ad-PTEN may be a potential therapeutic for treatment of colorectal cancers.

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Section: Discussionsupporting

confidence: 92%

Section: Viral Production and Transduction Efficiencymentioning

confidence: 99%

Adenovirus-mediated transfer of the PTEN gene inhibits human colorectal cancer growth in vitro and in vivo

et al. 2003

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“…Induction of G 2 /M arrest by Ad-PTEN in cells that express wt-PTEN is not surprising and is in agreement with results of our recent studies. 12,30 However, PTEN induction of G 2 /M phase was abrogated by caffeine in both tumor and normal cells. Caffeine-induced G 1 was significantly more common in normal CCD-18Co cells than in HCT116 p53 ðþ=þÞ cells, suggesting that caffeine had a stronger inhibitory effect on proliferation of CCD18Co cells proliferation than on that of HCT116 p53 ðþ=þÞ cells.…”

Section: Discussionmentioning

confidence: 99%

“…[36][37][38] It is possible that the results of previous studies are supported by the observation that p53 plays an important role in DNA damage-induced cell-cycle checkpoints and contributes to the prevention of polyploidy formation. [30][31][32][33][34][35][36][37][38][39][40][41] More recent studies have demonstrated that PTEN protects p53 from Mdm2, allows cells to respond to damage or mutation with an apoptotic response, and sensitizes cancer cells to chemotherapy. 41,43 In fact, Tsuchiya et al 43 showed that the synergistic antitumor effect of caffeine and cisplatin was enhanced by reintroduction of wild-type p53 into human osteosarcoma cells.…”

Section: Discussionmentioning

confidence: 99%

Adenovirus-mediated PTEN treatment combined with caffeine produces a synergistic therapeutic effect in colorectal cancer cells

et al. 2003

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The tumor suppressor phosphatase and tensin homologue deleted from chromosome 10 (PTEN) gene is a negative regulator of the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt/PKB) signaling pathway. Overexpression of PTEN in cancer cells results in cell-cycle arrest and cell death through inhibition of PI3K. Caffeine, a xanthine analogue, is well known to enhance the cytocidal and growth-inhibitory effects of DNA-damaging agents such as radiation, UV light, and anticancer agents on tumor cells by abrogating DNA-damage checkpoints through inhibition of ataxia-telangiectasia-mutated (ATM), and ATM and Rad3-related (ATR) kinase activity. In this study, we demonstrate that treatment with a combination of adenovirus-mediated transfer of PTEN (Ad-PTEN) and caffeine synergistically suppressed cell growth and induced apoptosis in colorectal cancer cells but not in normal colorectal fibroblast cells. This synergistic effect was induced through abrogation of G 2 /M arrest, downregulation of the Akt pathway, and modulation of the p44/42MAPK pathway. Thus, combined treatment with Ad-PTEN and caffeine is a potential therapy for colorectal cancer.

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“…In melanoma, allelic loss or altered expression of PTEN comprises 20% and 40% of melanoma tumors, respectively (Pollock et al 2002;Mikhail et al 2005;Slipicevic et al 2005;Goel et al 2006), although somatic point mutations and homozygous deletions are rarely observed. Functionally, ectopic expression of PTEN in PTEN-deficient melanoma cells can abolish phospho-AKT activity, induce apoptosis, and suppress growth, tumorigenicity, and metastasis (Robertson et al 1998;Stewart et al 2002;Stahl et al 2003; for review, see Robertson 2005). Correspondingly, germline or somatic inactivation of Pten in the mouse strongly promotes tumor phenotypes in multiple cell lineages (Di Cristofano et al 1998;Stambolic et al 1998;Podsypanina et al 1999;Ma et al 2005), including melanoma (You et al 2002).…”

Section: Pten Negative Regulator Of Phosphatidylinositol 3-kinase (Pmentioning

confidence: 99%

Malignant melanoma: genetics and therapeutics in the genomic era

2006

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Cell for cell, probably no human cancer is as aggressive as melanoma. It is among a handful of cancers whose dimensions are reported in millimeters. Tumor thickness approaching 4 mm presents a high risk of metastasis, and a diagnosis of metastatic melanoma carries with it an abysmal median survival of 6-9 mo. What features of this malignancy account for such aggressive behavior? Is it the migratory history of its cell of origin or the programmed adaptation of its differentiated progeny to environmental stress, particularly ultraviolet radiation? While the answers to these questions are far from complete, major strides have been made in our understanding of the cellular, molecular, and genetic underpinnings of melanoma. More importantly, these discoveries carry profound implications for the development of therapies focused directly at the molecular engines driving melanoma, suggesting that we may have reached the brink of an unprecedented opportunity to translate basic science into clinical advances. In this review, we attempt to summarize our current understanding of the genetics and biology of this disease, drawing from expanding genomic information and lessons from development and genetically engineered mouse models. In addition, we look forward toward how these new insights will impact on therapeutic options for metastatic melanoma in the near future. The diseaseMelanomas most often arise within epidermal melanocytes of the skin, although they can also derive from noncutaneous melanocytes such as those lining the choroidal layer of the eye, GI and GU mucosal surfaces, or the meninges. Melanoma is also among the more common causes of "metastatic cancer of unknown primary," which may reflect either a propensity to arise in unexpected sites along the neural crest migratory route, or rapid growth of poorly differentiated lesions arising from indolent or unrecognized cutaneous primary lesions. Clinical staging for primary cutaneous melanoma employs measurements of thickness (in millimeters), presence of ulceration, penetration through cutaneous layers, mitotic rate, evidence of "in transit" metastasis, tumor spread to draining lymph nodes, and evidence of distant metastasis. Management issues in melanoma can be classified in terms of prevention, diagnosis, local disease management, and treatment of metastatic disease.In view of the epidemiological and emerging experimental evidence linking melanoma incidence to UV exposure and skin phototype, prevention and screening strategies represent key areas for reduction of disease incidence and severity. For most cutaneous melanomas in the so-called radial growth phase (e.g., thin melanomas), surgical removal affords curative treatment. In contrast, a significant fraction of patients diagnosed with intermediate-thickness (2-4 mm) cutaneous melanoma eventually succumb to recurrence at regional or distant sites.Critical biological questions facing the melanoma research community include: (1) What genetic and environmental factors contribute to and/or modulate risk of melanom...

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PI3K Blockade by Ad-PTEN Inhibits Invasion and Induces Apoptosis in Radial Growth Phase and Metastatic Melanoma Cells

Cited by 75 publications

References 37 publications

Adenovirus-mediated transfer of the PTEN gene inhibits human colorectal cancer growth in vitro and in vivo

Adenovirus-mediated transfer of the PTEN gene inhibits human colorectal cancer growth in vitro and in vivo

Adenovirus-mediated PTEN treatment combined with caffeine produces a synergistic therapeutic effect in colorectal cancer cells

Malignant melanoma: genetics and therapeutics in the genomic era

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