Secreted transforming growth factor beta2 activates NF-kappaB, blocks apoptosis, and is essential for the survival of some tumor cells.

Department of Molecular Biology, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 06/2004; 101(18):7112-7. DOI: 10.1073/pnas.0402048101
Source: PubMed

ABSTRACT The basis of constitutive activation of NF-kappaB, essential for survival and resistance to apoptosis in many tumors, is not well understood. We find that transforming growth factor beta2 (TGFbeta2), predominantly in its latent form, is secreted by several different types of tumor cell lines that exhibit constitutively active NF-kappaB and that TGFbeta2 potently stimulates the activation of NF-kappaB in reporter cells. Suppression of TGFbeta2 expression by small interfering RNA kills prostate cancer PC3 cells, indicating that the TGFbeta2-NF-kappaB pathway is important for their viability. These findings identify TGFbeta2 as a potential target for therapeutic strategies to inhibit the growth of tumor cells that depend on constitutively active NF-kappaB, or to sensitize them to treatment with cytotoxic drugs.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Colon cancer is one of the third most common cancer in man, the second most common cancer in women worldwide, and the second leading cause of mortality in the USA. There are a number of molecular pathways that have been implicated in colon carcinogenesis, including TGF-β/Smad signaling pathway. TGF-β (transforming growth factor-beta) signaling pathway has the potential to regulate various biological processes including cell growth, differentiation, apoptosis, extracellular matrix modeling, and immune response. TGF-β signaling pathway acts as a tumor suppressor, but alterations in TGF-β signaling pathway promotes colon cancer cell growth, migration, invasion, angiogenesis, and metastasis. Here we review the role of TGF-β signaling cascade in colon carcinogenesis and multiple molecular targets of curcumin in colon carcinogenesis. Elucidation of the molecular mechanism of curcumin on TGF-β signaling pathway-induced colon carcinogenesis may ultimately lead to novel and more effective treatments for colon cancer.
    Tumor Biology 03/2014; · 2.84 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The development of novel cancer therapeutics is often plagued by discrepancies between drug efficacies obtained in preclinical studies and outcomes of clinical trials. The inconsistencies can be attributed to a lack of clinical relevance of the cancer models used for drug testing. While commonly used in vitro culture systems are advantageous for addressing specific experimental questions, they are often gross, fidelity-lacking simplifications that largely ignore the heterogeneity of cancers as well as the complexity of the tumor microenvironment. Factors such as tumor architecture, interactions among cancer cells and between cancer and stromal cells, and an acidic tumor microenvironment are critical characteristics observed in patient-derived cancer xenograft models and in the clinic. By mimicking these crucial in vivo characteristics through use of 3D cultures, co-culture systems and acidic culture conditions, an in vitro cancer model/microenvironment that is more physiologically relevant may be engineered to produce results more readily applicable to the clinic.
    Advanced Drug Delivery Reviews 10/2014; · 12.71 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Increased expression of transforming growth factor-β (TGF-β) isoforms in human endometrial cancer correlates with decreased survival and poor prognosis. Progesterone has been shown to exert a chemoprotective effect against endometrial cancer and previous animal models have suggested that these effects are accompanied by changes in TGF-β. The goal of this study was to characterize the effect of progesterone on TGF-β signaling pathway components and on TGF-β-induced pro-tumorigenic activities in endometrial cancer cell lines. Progesterone significantly decreased expression of three TGF-β isoforms at 72 hours after treatment except for TGF-β2 in HEC-1B and TGF-β3 in Ishikawa cells. Progesterone treatment for 120 hours attenuated expression of the three isoforms in all cell lines. Progesterone exposure for 72 hours reduced expression of TGF-β receptors in HEC-1B cells and all but TGF-βR1 in Ishikawa cells. Progesterone reduced TGF-βR3 expression in RL-95 cells at 72 hours, but TGF-βR1 and βR2 expression levels were not affected by progesterone at any time point. SMAD2/3 and pSMAD2/3 were substantially reduced at 72 hours in all cell lines. SMAD4 expression was reduced in RL-95 cells at 24 hours and in HEC-1B and Ishikawa cells at 72 hours following progesterone treatment. Furthermore, progesterone effectively inhibited basal and TGF-β1-induced cancer cell viability and invasion, which was accompanied by increased E-cadherin and decreased vimentin expression. An inhibitor of TGF-βRI blocked TGF-β1-induced effects on cell viability and invasion and attenuated antitumor effects of progesterone. These results suggest that down-regulation of TGF-β signaling is a key mechanism underlying progesterone inhibition of endometrial cancer growth.
    Cancer Prevention Research 07/2014; · 5.27 Impact Factor

Full-text (2 Sources)

Available from
May 21, 2014