Article

The PTEN/Akt Pathway Dictates the Direct αVβ3-Dependent Growth-Inhibitory Action of an Active Fragment of Tumstatin in Glioma Cells In vitro and In vivo

Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, United States
Cancer Research (Impact Factor: 9.28). 01/2007; 66(23):11331-40. DOI: 10.1158/0008-5472.CAN-06-1540
Source: PubMed

ABSTRACT The collagen type IV cleavage fragment tumstatin and its active subfragments bind to integrin alpha(V)beta(3) and inhibit activation of focal adhesion kinase, phophoinositol-3 kinase, Akt, and mammalian target of rapamycin (mTOR) in what is thought to be an endothelial cell-specific manner. The resultant endothelial cell apoptosis accounts for the ability of tumstatin to function as an endogenous inhibitor of angiogenesis and an indirect suppressor of tumor growth. We hypothesized that the inability of tumstatin to directly suppress tumor cell growth might be the result of the constitutive activation of the Akt/mTOR pathway commonly seen in tumors. Consistent with this idea, several integrin alpha(V)beta(3)-expressing glioma cell lines with PTEN mutations and high levels of phospho-Akt (pAkt) were unaffected by exposure to an active fragment of tumstatin (T3), whereas alpha(V)beta(3)-expressing glioma cell lines with a functional PTEN/low levels of pAkt exhibited T3-induced growth suppression that could be bypassed by small interfering RNA-mediated suppression of PTEN, introduction of a constitutively expressed Akt, or introduction of the Akt and mTOR target eukaryotic translation initiation factor 4E. The direct tumor-suppressive actions of T3 were further shown in an alpha(V)beta(3)-deficient in vivo mouse model in which T3, while unable to alter the tumstatin-insensitive vasculature contributed by the alpha(V)beta(3)-deficient host, nonetheless suppressed the growth and proliferative index of i.c. implanted alpha(V)beta(3)-expressing PTEN-proficient glioma cells. These results show that tumstatin, previously considered to be only an endogenous inhibitor of angiogenesis, also directly inhibits the growth of tumors in a manner dependent on Akt/mTOR activation.

0 Followers
 · 
62 Views
  • Source
    • "The small interfering RNA (siRNA) target sequence of human PTEN gene was 59-AACAGTAGAGGAGCCGTCAAA-39 (Kawaguchi et al., 2006). The pSilencer 4.1-CMV neo siRNA expression vector (Ambion) with the inserted RNAi (RNA interference ) cassette was transiently transfected into BGC823 cells using Lipofectamine 2000. "
    [Show abstract] [Hide abstract]
    ABSTRACT: NaB (sodium butyrate) inhibits cell proliferation and induces differentiation in a variety of tumour cells. In this study, we aimed to determine whether NaB induced differentiation and regulated the expression of the mucosal factor MUC2 through the PTEN/PI3K (phosphoinositide 3-kinase) pathway. BGC823 cells treated with NaB for 24-72 h showed marked inhibition of cell proliferation and alteration in cellular morphology. NaB treatment markedly increased the expression of PTEN and MUC2, but it decreased the expression of PI3K. These effects were enhanced by intervention with PI3K inhibitors and were reduced by intervention with PTEN siRNA. Hence, we conclude that NaB increased PTEN expression, promoted the expression of MUC2 and induced the differentiation of gastric cancer cells through the PTEN/PI3K signalling pathway.
    Cell Biology International 12/2010; 34(12):1141-5. DOI:10.1042/CBI20090481 · 1.64 Impact Factor
  • Source
    • "The cryptic RGD site within the N-terminal somatomedin domain of vitronectin can be recognized by a number of integrins including avb3, avb5, and avb1. A wealth of evidence has implicated av integrins such as avb3 and avb5 in regulating both tumor metastasis and angiogenesis (Brooks, 2002; Akalu et al., 2005; Kawaguchi et al., 2006). Integrin avb3 signaling has been shown to modulate gene expression, tumor cell invasion, proliferation, and survival (Brooks, 2002; Akalu et al., 2005). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Evidence is accumulating that the malignant phenotype of a given tumor is dependent not only on the intrinsic characteristics of tumor cells, but also on the cooperative interactions of non-neoplastic cells, soluble secreted factors and the non-cellular solid-state ECM network that comprise the tumor microenvironment. Given the ability of the tumor microenvironment to regulate the cellular phenotype, recent efforts have focused on understanding the molecular mechanisms by which cells sense, assimilate, interpret, and ultimately respond to their immediate surroundings. Exciting new studies are beginning to unravel the complex interactions between the numerous cell types and regulatory factors within the tumor microenvironment that function cooperatively to control tumor cell invasion and metastasis. Here, we will focus on studies concerning a common theme, which is the central importance of the non-cellular solid-state compartment as a master regulator of the malignant phenotype. We will highlight the non-cellular solid-state compartment as a relatively untapped source of therapeutic and imaging targets and how cellular interactions with these targets may regulate tumor metastasis.
    Journal of Cellular Physiology 11/2007; 213(2):391-402. DOI:10.1002/jcp.21222 · 3.87 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The concept of anti-angiogenesis therapy was introduced by Judah Folkman in 1971 and since then, a plethora of pro- and anti-angiogenic factors have been identified. In the recent years, it has become clear that angiogenesis, the formation of new capillaries from a pre-existing capillary network, is highly regulated by the action of pro- and anti-angiogenic factors. In the healthy adult organism the "angiogenic-switch" is likely turned "Off", i. e. anti-angiogenic factors are likely counteracting the pro-angiogenic factors resulting in a non-angiogenic state. Angiogenesis is encountered during wound healing processes, the female menstrual cycle and endometrial remodeling, as well as during embryonic development and organ growth. In the pathological setting, angiogenesis plays an important role in different diseases like rheumatoid arthritis, psoriasis, macular degeneration, diabetic retinopathy, and tumor growth. In this regard, recent studies have described several endogenous inhibitors of angiogenesis, with a subset derived from extracellular matrix (ECM) proteins. This review will particularly focus on the type IV collagen-derived angiogenesis inhibitors Arresten, Canstatin and Tumstatin.
    Microvascular Research 09/2007; 74(2-3):85-9. DOI:10.1016/j.mvr.2007.05.005 · 2.43 Impact Factor
Show more