(653f) A Novel Mathematical Model of TGF-β-Induced Apoptosis Signaling Pathways

Transforming growth factor β (TGF-β) signaling plays a vital role in regulating a wide range of cellular processes in both healthy and cancerous cells. In normal or pre-malignant epithelia, TGF-β is well known to inhibit cell proliferation and to induce programmed cell death (or apoptosis). However, in late stages of cancer progression, the role of TGF-β appears to shift in favor of tumor promotion, apparently facilitating epithelial-to-mesenchymal transition (EMT), motility and invasion. While the full details of the mechanisms underlying how TGF-β induces such diverse and contradictory responses during cancer progression are not yet completely elucidated, recent computational studies of the canonical SMAD-mediated signaling pathway have produced plausible explanations that have significantly improved our understanding of these mechanisms [1]. Still, many aspects of TGF-β’s role in healthy and cancerous cells remain completely unexplored, including how TGF-β elicits pro-apoptotic effects and how such effects are markedly weakened in cancer cells. A coherent quantitative understanding of the mechanism of TGF-β-induced apoptosis, an indispensable component of any potentially successful TGF-β-mediated targeted cancer treatment, is completely unavailable at present.

In this study, we present for the first time a mathematical modeling framework for understanding the complex signaling behavior of TGF-β-induced apoptosis. The model incorporates various TGF-β branch pathways, including the TAK1-MKK3/6-p38, Smad-GADD45β-MTK1, and putative ARTS pathways, which are coupled with downstream caspase activation cascades and the mitochondrial pathway. The model provides quantitative insight into how TGF-β-induced apoptosis can be modulated and regulated. Model analysis shows that upon TGF-β stimulation, the role of the TAK1-MKK3/6-p38 cascade-driven apoptosis pathway in executing cell death is predominant over Smad-mediated or michochondrial mechanisms. The model also predicts possible dynamic behavior of the TGF-β-driven apoptosis signaling in cancerous cells. Of particular importance is the model prediction that a significant reduction in the level of functional TGF-β receptors alone is insufficient for cancer cells to avoid cell death, suggesting that additional abnormal alterations in other intracellular mechanisms such as (i) downregulation of caspases, (ii) upregulation of caspase inhibitors, and/or (iii) downregulation of upstream p38 MAPK pathway effectors, may need to occur in tandem for cancer cells to evade apoptosis successfully. Finally, the model indicates that the ARTS pathway may play an essential role in suppressing the anti-apoptotic effect of XIAP, a potent caspase inhibitor, leading us to propose the ARTS pathway as a promising therapeutic option.

[1]        Chung, S., Miles, F., Sikes, R., Cooper, C., Farach-Carson, M. and Ogunnaike, B. (2009). Quantitative modeling and analysis of the transforming growth factor β signaling pathway. Biophys J 96, 1733-1750.