Introduction of wild-type p53 enhances thrombospondin-1 expression in human glioma cells

Harada, Hironobu; Nakagawa, Kou; Saito, Masahiro; Kohno, Shohei; Nagato, Shigeyuki; Furukawa, Koji; Kumon, Yoshiaki; Hamada, Katsuyuki; Ohnishi, Takanori

doi:10.1016/s0304-3835(02)00592-x

Cited by 29 publications

(20 citation statements)

References 15 publications

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“…While altered TSP-1 expression previously has not been reported to affect taxane cytotoxicity, we noticed that certain genes that modulate taxol effects (e.g., p53 and Id1) (Wahl et al 1996;Cheung et al 2004) are among those identified in separate experiments as regulators of TSP-1 abundance (Volpert et al 2002a;Harada et al 2003). Interestingly, TSP-1 also has been observed recently to be elevated during taxane treatment of cancers (Yoo et al 2002(Yoo et al , 2005Damber et al 2006), leading to the suggestion that its anti-angiogenic effects may enhance the lethality of taxol therapy.…”

Section: Txr1 Effect On Taxane Cytotoxicity Is Mediated Through Tsp-1mentioning

confidence: 65%

Txr1: a transcriptional regulator of thrombospondin-1 that modulates cellular sensitivity to taxanes

Lih¹,

Wei²,

Cohen³

2006

Genes Dev.

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Using transcripts initiated at a chromosomally integrated retrovirus-based promoter to perturb gene expression randomly in human prostate cancer cells, we isolated cell clones resistant to taxane lethality and discovered the role of a previously uncharacterized gene, txr1, in this phenotype. We show that txr1 impedes taxane-induced apoptosis in tumor cells by transcriptionally down-regulating the production of thrombospondin-1 (TSP-1)-known earlier for both its anti-angiogenic and proapoptotic actions. Decrease of Txr1 or treatment with TSP-1 or TSP-1 mimetic peptide sensitized cells to taxane cytotoxicity by activating signaling through the CD47 receptor (also known as the integrin-associated protein), whereas interference with CD47 function reduced taxane-induced cell death. Cellular abundance of Txr1 and TSP-1 varied inversely, and alteration of the level of both proteins correlated highly with taxol resistance in 13 of 19 NCI-60 cancer cell lines. Our results reveal a hitherto unsuspected mechanism of taxane resistance, elucidate the role of txr1 in this resistance, and identify txr1 as a regulator of TSP-1 production and an agent for its chemotherapeutic modulation.[Keywords: Thrombospondin-1; CD47; taxanes; microarray; angiogenesis; Txr1] Supplemental material is available at http://www.genesdev.org. Taxanes are a family of major chemotherapeutic agents that have anti-neoplastic effects against a wide spectrum of human cancers (Rowinsky 1997). The anti-proliferative actions of the two clinically employed taxanes, paclitaxel (taxol) and docetaxel, stem from their ability to interact with ␤-tubulin and promote tubulin polymerization and stability; this event blocks cell cycling at the G 2 -M transition and results in eventual cell death by apoptosis (Horwitz 1992). Despite a dramatic response of susceptible tumors to initial treatment with taxanes, the subsequent development of resistance has proved to be a major limitation to long-term use of these agents as anticancer drugs (Horwitz et al. 1993). A widely studied mechanism associated with such resistance is the exclusion of taxanes and other drugs from cells by up-regulation of ATP-dependent cell membrane P-glycoproteins (i.e., transporter-related multidrug resistance [MDR]) (Bradley and Ling 1994). Genetic mutations that interfere with the binding of taxanes to microtubules have also been extensively investigated as a cause of taxol resistance (Giannakakou et al. 1997;Kavallaris et al. 1997;Ranganathan et al. 1998;Monzo et al. 1999).In recent years, several approaches that use functionbased screens for the discovery of cellular genes whose inactivation or overexpression yields phenotypic properties of interest have been developed (Li and Cohen 1996;Kimchi 2003;Primiano et al. 2003;Berns et al. 2004;Lu et al. 2004). One of these (Li and Cohen 1996) uses an experimentally regulated chromosomally integrated virus-based promoter to modulate the expression of genes at the site of viral insertion. Using this approach, we identified a previously unknown gene, tx...

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Section: Txr1 Effect On Taxane Cytotoxicity Is Mediated Through Tsp-1mentioning

confidence: 65%

Txr1: a transcriptional regulator of thrombospondin-1 that modulates cellular sensitivity to taxanes

Lih¹,

Wei²,

Cohen³

2006

Genes Dev.

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“…Among these genes were three regulated by p53. Expression of both thrombospondin-1 and maspin, inhibitors of angiogenesis, has been shown to be positively regulated by p53, whereas expression of VEGF, an inducer of angiogenesis, has been shown to be negatively regulated by p53 via the HIF-1 alpha transcription factor (Ravi et al, 2000;Zou et al, 2000;Harada et al, 2003). On the microarray membranes, levels of thrombospondin-1 and maspin were decreased, while levels of VEGF were increased in cells expressing HPV 16 E6 and E7.…”

Section: Resultsmentioning

confidence: 99%

Expression of human papillomavirus type 16 E6 and E7 oncoproteins in primary foreskin keratinocytes is sufficient to alter the expression of angiogenic factors

2004

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Human papillomavirus (HPV) 16 is involved in causing cervical cancer. The E6 and E7 proteins of HPV 16 immortalize human keratinocytes and this is due, at least in part, to inactivation of the tumor suppressor proteins p53 and pRB. These tumor suppressor proteins also regulate the expression of pro-and antiangiogenic factors by cells. For this reason, experiments were conducted to determine whether the expression of E6 and E7 in primary keratinocytes alters the phenotype of these cells such that they express diminished levels of antiangiogenic factors and/or increased levels of proangiogenic factors. To avoid variances in experimental observations, pools of human foreskin keratinocytes from multiple sources were infected with recombinant retrovirus expressing HPV 16 E6 and E7 or control retrovirus. Gene array analysis, RT-PCR, ELISAs and Western blotting showed that in cells expressing HPV 16 E6 and E7, expression levels of two potent angiogenesis inhibitors, thrombospondin-1 and maspin, were lower compared to controls. Additionally, major angiogenesis inducers, interleukin-8 and vascular endothelial growth factor (VEGF), were increased relative to controls. VEGF can be produced as multiple splice variants, all of which are required for the formation of patent blood vessels. The expression of HPV 16 E6 and E7 in keratinocytes augmented expression of VEGF 121, 145, 165 and 189. These observations show that HPV 16 E6 and E7 alter the phenotype of primary keratinocytes, diminishing expression of inhibitors and increasing expression of inducers of angiogenesis. This altered phenotype may permit keratinocytes infected by HPV 16 to play a role in the progression of cancer by permitting tumors to acquire a blood supply permissive of growth and spread.

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“…However, TGF-β signaling downregulates TIMP expression [35], and the activation of Cox-2 has been recently shown to suppress p53 [58]. As p53 induces the angiogenesis inhibitor THBS-1 and downregulates HIF-1α [31, 59], the activation of PMN, which leads to the induction of Cox-2 activity, may shift the balance between the pro- and antiangiogenic activities of human PMN towards the proangiogenic potential.…”

Section: Discussionmentioning

confidence: 99%

The Proangiogenic Capacity of Polymorphonuclear Neutrophils Delineated by Microarray Technique and by Measurement of Neovascularization in Wounded Skin of CD18-Deficient Mice

et al. 2005

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Growing evidence supports the concept that polymorphonuclear neutrophils (PMN) are critically involved in inflammation-mediated angiogenesis which is important for wound healing and repair. We employed an oligonucleotide microarray technique to gain further insight into the molecular mechanisms underlying the proangiogenic potential of human PMN. In addition to 18 known angiogenesis-relevant genes, we detected the expression of 10 novel genes, namely midkine, erb-B2, ets-1, transforming growth factor receptor-β₂ and -β₃, thrombospondin, tissue inhibitor of metalloproteinase 2, ephrin A2, ephrin B2 and restin in human PMN freshly isolated from the circulation. Gene expression was confirmed by the RT-PCR technique. In vivo evidence for the role of PMN in neovascularization was provided by studying neovascularization in a skin model of wound healing using CD18-deficient mice which lack PMN infiltration to sites of lesion. In CD18-deficient animals, neovascularization was found to be significantly compromised when compared with wild-type control animals which showed profound neovascularization within the granulation tissue during the wound healing process. Thus, PMN infiltration seems to facilitate inflammation-mediated angiogenesis which may be a consequence of the broad spectrum of proangiogenic factors expressed by these cells.

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Introduction of wild-type p53 enhances thrombospondin-1 expression in human glioma cells

Cited by 29 publications

References 15 publications

Txr1: a transcriptional regulator of thrombospondin-1 that modulates cellular sensitivity to taxanes

Txr1: a transcriptional regulator of thrombospondin-1 that modulates cellular sensitivity to taxanes

Expression of human papillomavirus type 16 E6 and E7 oncoproteins in primary foreskin keratinocytes is sufficient to alter the expression of angiogenic factors

The Proangiogenic Capacity of Polymorphonuclear Neutrophils Delineated by Microarray Technique and by Measurement of Neovascularization in Wounded Skin of CD18-Deficient Mice

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