Related Experiment Video
Updated: Jun 10, 2026
Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
Published on: October 27, 2020
XIAP gene expression and function is regulated by autocrine and paracrine TGF-beta signaling
Céline Van Themsche1, Parvesh Chaudhry, Valérie Leblanc
1Research group in Molecular Oncology and Endocrinology, Department of Chemistry-Biology, University of Quebec at Trois-Rivieres, Trois-Rivières, Quebec, Canada.
Background:
X-linked inhibitor of apoptosis protein (XIAP) is often overexpressed in cancer cells, where it plays a key role in survival and also promotes invasiveness. To date however, the extracellular signals and intracellular pathways regulating its expression and activity remain incompletely understood. We have previously showed that exposure to each of the three TGF-beta (transforming growth factor beta) isoforms upregulates XIAP protein content in endometrial carcinoma cells in vitro. In the present study, we have investigated the clinical relevance of TGF-beta isoforms in endometrial tumours and the mechanisms through which TGF-beta isoforms regulate XIAP content in uterine cancer cells.
Methods:
TGF-beta isoforms immunoreactivity in clinical samples from endometrial tumours was assessed using immunofluorescence. Two model cancer cell lines (KLE endometrial carcinoma cells and HeLa cervical cancer cells) and pharmacological inhibitors were used to investigate the signalling pathways regulating XIAP expression and activity in response to autocrine and paracrine TGF-beta in cancer cell.
Results:
We have found immunoreactivity for each TGF-beta isoform in clinical samples from endometrial tumours, localizing to both stromal and epithelial/cancer cells. Blockade of autocrine TGF-beta signaling in KLE endometrial carcinoma cells and HeLa cervical cancer cells reduced endogenous XIAP mRNA and protein levels. In addition, each TGF-beta isoform upregulated XIAP gene expression when given exogenously, in a Smad/NF-kappaB dependent manner. This resulted in increased polyubiquitination of PTEN (phosphatase and tensin homolog on chromosome ten), a newly identified substrate for XIAP E3 ligase activity, and in a XIAP-dependent decrease of PTEN protein levels. Although each TGF-beta isoform decreased PTEN content in a XIAP- and a Smad-dependent manner, decrease of PTEN levels in response to only one isoform, TGF-beta3, was blocked by PI3-K inhibitor LY294002.
Conclusions:
XIAP gene expression and function is positively regulated by exposure to the three TGF-beta isoforms in a Smad-dependent manner, similar to constitutive XIAP gene expression which depends on autocrine TGF-beta/Smad signalling.
Insights
Transforming growth factor beta (TGF-β) isoforms upregulate X-linked inhibitor of apoptosis protein (XIAP) in uterine cancers. This TGF-β/XIAP pathway impacts PTEN levels, offering potential therapeutic targets.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- X-linked inhibitor of apoptosis protein (XIAP) is overexpressed in cancer, promoting survival and invasiveness.
- Extracellular signals and intracellular pathways regulating XIAP remain unclear.
- Transforming growth factor beta (TGF-β) isoforms upregulate XIAP in endometrial cancer cells.
Purpose of the Study:
- Investigate the clinical relevance of TGF-β isoforms in endometrial tumors.
- Elucidate mechanisms of TGF-β-mediated XIAP regulation in uterine cancer cells.
Main Methods:
- Immunofluorescence assessed TGF-β isoform immunoreactivity in endometrial tumors.
- Used KLE and HeLa cancer cell lines with pharmacological inhibitors to study signaling pathways.
- Investigated autocrine and paracrine TGF-β signaling effects on XIAP.
Main Results:
- All three TGF-β isoforms showed immunoreactivity in endometrial tumors (stromal and epithelial cells).
- Blocking autocrine TGF-β signaling reduced XIAP mRNA and protein.
- Exogenous TGF-β isoforms upregulated XIAP via Smad/NF-κB, decreasing PTEN levels.
Conclusions:
- XIAP expression and function are positively regulated by TGF-β isoforms in a Smad-dependent manner.
- Constitutive XIAP expression relies on autocrine TGF-β/Smad signaling.
- TGF-β signaling impacts PTEN levels through XIAP, with TGF-β3 effects modulated by PI3-K.
Related Concept Videos
01:16TGF - β Signaling Pathway
01:01Autocrine Signaling
Autocrine Signaling in Macrophages
Under normal physiological conditions, autocrine signaling is essential for maintaining homeostasis. This process is well characterized in...
01:01Autocrine Signaling
Autocrine Signaling in Macrophages
Under normal physiological conditions, autocrine signaling is essential for maintaining homeostasis. This process is well characterized in...
01:24Regulation of Angiogenesis and Blood Supply
02:54Canonical Wnt Signaling Pathway
01:19Interactions Between Signaling Pathways
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...