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Mechanisms of Cell Cycle Regulation by TGF-β Disabled in Cancer

  • Chapter
Transforming Growth Factor-β in Cancer Therapy, Volume I

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

Disabling the TGF-β signaling pathway is a widespread means by which carcinoma cells subvert the normally potent growth arresting effect of TGF-β to enable cancer cell growth. We have shown disrupted TGF-β signaling concomitant with loss of growth inhibition by TGF-β occurs early in endometrial carcinogenesis. As an effector of cell cycle arrest, TGF-β inhibits synthesis of certain cyclin/cdks and directly induces cdk inhibitors (CDKI), such as p15Ink4b(p15) and p21Waf1/Cip1(p21), to inhibit phosphorylation of Rb, thereby preventing progression to S phase. Although the level of the CDKI, p27Kip1(p27) is increased in a variety of TGF-β treated cells, evidence for the regulation of p27 by TGF-β in epithelial cells has largely been indirect. Now, we show that TGF-β dosedependently increases both nuclear and cytoplasmic levels of p27 in primary cultures of normal endometrial epithelial cells (EECs) by preventing its degradation through the downregulation of Skp2 and cks1, critical components of the SCFskp2 complex, that target p27 for ubiquitin-mediated degradation. Thus, the levels of p27 and Cks1/Skp2 are inversely regulated by TGF-β to achieve normal cell cycle arrest in late G1. In contrast, the lack of TGF-β signaling in primary endometrial carcinoma (ECA) cells promotes rapid proteasomal degradation of p27 for uncontrolled cell growth. The increase in p27 and decrease in Cks1/Skp2 is recapitulated in vivo in normal secretory phase endometrium (SE) compared to all grades of ECA, which show the reverse. Transient transfection of Smad2 into a TGF-β-responsive ECA cell line, HEC-1A, decreased the levels of cks1 and a small molecule inhibitor of TGF-β receptor I kinase (SD-208) blocked the ability of TGF-β to decrease cks1 and increase p27 indicating that these effects result from direct classic TGF-β signaling. Importantly, knocking down p27 with a siRNA approach blocked TGF-β mediated growth inhibition in HEC-1A, further substantiating that TGF-β mediates growth inhibition through p27 in these cells. In addition, we further show that estrogen causes MAPK-driven ubiquitin-mediated degradation of p27 for proliferation and that progesterone induces marked accumulation of p27 to block cell growth. Thus, our results suggest that TGF-β and ovarian hormones converge on the regulation of intracellular p27 levels as a major target for endometrial growth. Because ECA is an estrogen-induced cancer, related to unopposed estrogen, and progesterone is therapeutic for this disease, we propose that the pathogenesis of ECA may be related to both the lack of TGF-β signaling and the absence of progesterone (as in menopause and anovulation), causing continuous estrogen-driven proteasomal degradation of p27. Finally, soluble mediators derived from stromal cells in the ECA tumor microenvironment, but not from normal stromal cells, decrease the levels of p27 and increase the levels of cks1, while increasing growth of HEC-1A cells, implicating a role for stromal cells in endometrial carcinogenesis.

Temporally regulated ubiquitin-mediated destruction of cell cycle proteins precisely control the levels of proteins to block or induce cell cycle progression. Our results suggest that TGF-β negatively regulates destruction of p27 protein to maintain sufficient levels of this CDKI for cell cycle arrest. As such, TGF-β facilitates a counter-destruction mechanism of cell cycle regulation. As Skp2 and cks1 are markedly increased in ECA (and other human cancers) perpetuating destruction of p27 thereby permitting uncontrolled growth, these proteins may be novel rational targets for the prevention and therapy of this cancer.

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  1. Departments of Medicine and Pathology, New York University Cancer Institute, New York University School of Medicine, New York, NY, USA

    Leslie I. Gold PhD & Jon Lecanda PhD

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Gold, L.I., Lecanda, J. (2008). Mechanisms of Cell Cycle Regulation by TGF-β Disabled in Cancer. In: Transforming Growth Factor-β in Cancer Therapy, Volume I. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1007/978-1-59745-292-2_14

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