Inhibition of BMP and of TGFβ receptors downregulates expression of XIAP and TAK1 leading to lung cancer cell death.

Abstract

BACKGROUND:

Bone morphogenetic proteins (BMP) are embryonic proteins that are part of the transforming growth factor (TGFβ) superfamily, which are aberrantly expressed in many carcinomas. Inhibition of BMP receptors with small molecule inhibitors decreases growth and induces death of lung cancer cells, which involves the downregulation of Id1 and Id3 by a Smad dependent mechanism. Developmentally, BMP and TGFβ signaling utilizes Smad-1/5 independent mechanisms to stabilize the expression of X-linked inhibitor of apoptosis protein (XIAP) and activate TGFβ activated kinase 1 (TAK1), which are known to be potent inhibitors of apoptosis. The role of BMP signaling in regulating XIAP and TAK1 in cancer cells is poorly understood. Furthermore, the interaction between the BMP and TGFβ signaling cascades in regulating the activation of TAK1 in cancer cells has not been elucidated.

METHODS:

Feedback regulation between the BMP and TGFβ signaling pathways and their regulation of XIAP, TAK1, and Id1 were examined in lung cancer cells utilizing siRNA and inhibitors targeting BMP type I receptors, inhibitors of BMP and TGFβ type I receptors, and an inhibitor of BMP and TGFβ type I and type II receptors.

RESULTS:

We show that upon inhibition of BMP signaling in lung cancer cells, the TGFβ signaling cascade is activated. Both the BMP and TGFβ pathways activate TAK1, which then increases the expression of Id1. Inhibition of TGFβ signaling increased Id1 expression except when BMP signaling is suppressed, which then causes a dose-related decrease in the expression of Id1. Inhibition of both BMP and TGFβ signaling enhances the downregulation of TAK1. Our data also suggests that the blockade of the BMP type II receptor enhances the downregulation XIAP, which is important in decreasing the activity of TAK1. Knockdown studies demonstrate that both XIAP and TAK1 regulate the survival of lung cancer cells.

CONCLUSIONS:

This paper highlights that targeting the BMP and TGFβ type I and type II receptors causes a downregulation of XIAP, TAK1, and Id1 leading to cell death of lung cancer cells. Small molecule inhibitors targeting the BMP and TGFβ receptors represents a potential novel means to treat cancer patients.

• Authors: Dave J Augeri, Elaine Langenfeld, Monica Castle, John A Gilleran, John Langenfeld
• Journal: Molecular cancer (Mol Cancer) Vol. 15 Pg. 27 (Apr 06 2016) ISSN: 1476-4598 [Electronic] England
• PMID: 27048361 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ID1 protein, human
• Inhibitor of Differentiation Protein 1
• Receptors, Transforming Growth Factor beta
• Smad2 Protein
• Small Molecule Libraries
• X-Linked Inhibitor of Apoptosis Protein
• XIAP protein, human
• src-Family Kinases
• MAP Kinase Kinase Kinases
• MAP kinase kinase kinase 7
• Bone Morphogenetic Protein Receptors, Type I
• Mitogen-Activated Protein Kinase Kinases

Topics

• Animals
• Bone Morphogenetic Protein Receptors, Type I (metabolism)
• Cell Death (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Down-Regulation (drug effects)
• Female
• Humans
• Inhibitor of Differentiation Protein 1 (metabolism)
• Inhibitory Concentration 50
• Lung Neoplasms (metabolism, pathology)
• MAP Kinase Kinase Kinases (metabolism)
• Mice, Nude
• Mitogen-Activated Protein Kinase Kinases (metabolism)
• Phosphorylation (drug effects)
• Receptors, Transforming Growth Factor beta (metabolism)
• Signal Transduction (drug effects)
• Smad2 Protein (metabolism)
• Small Molecule Libraries (pharmacokinetics, pharmacology)
• X-Linked Inhibitor of Apoptosis Protein (metabolism)
• Xenograft Model Antitumor Assays
• src-Family Kinases (metabolism)