Small molecule antagonist of the bone morphogenetic protein type I receptors suppresses growth and expression of Id1 and Id3 in lung cancer cells expressing Oct4 or nestin.

Abstract

BACKGROUND:

Bone morphogenetic proteins (BMP) are embryonic morphogens that are aberrantly expressed in lung cancer. BMPs mediate cell fate decisions and self-renewal of stem cells, through transcription regulation of inhibitor of differentiation protein/DNA binding proteins (Id1-3). Inhibition of BMP signaling decreases growth and induces cell death of lung cancer cells lines by downregulating the expression of Id proteins. It is not known whether the BMP signaling cascade regulates growth and the expression of Id proteins of lung cancer cells expressing the stem cell markers Oct4 and/or nestin.

METHODS:

Lung cancer cells expressing Oct4 or nestin were isolated from lung cancer cell lines by stably transfecting the Oct4 promoter or nestin promoter expression vectors that induce expression of the green fluorescent protein reporter.

RESULTS:

Our studies suggest that lung cancer cells expressing Oct4 or nestin are different cell populations. Microarray and quantitative RT-PCR demonstrated that the expression of specific stem cell markers were different between isolated Oct4 and nestin cells. Both the Oct4 and nestin populations were more tumorigenic than controls but histologically they were quite different. The isolated Oct4 and nestin cells also responded differently to inhibition of BMP signaling. Blockade of BMP signaling with the BMP receptor antagonist DMH2 caused significant growth inhibition of both the Oct4 and nestin cell populations but only increased cell death in the nestin population. DMH2 also induced the expression of nestin in the Oct4 population but not in the nestin cells. We also show that BMP signaling is an important regulator of Id1 and Id3 in both the Oct4 and nestin cell populations. Furthermore, we show that NeuN is frequently expressed in NSCLC and provide evidence suggesting that Oct4 cells give rise to cancer cells expressing nestin and/or NeuN.

CONCLUSION:

These studies show that although biologically different, BMP signaling is growth promoting in cancer cells expressing Oct4 or nestin. Inhibition of BMP signaling decreases expression of Id proteins and suppresses growth of cancer cells expressing Oct4 or Nestin. Small molecule antagonists of the BMP type I receptors represent potential novel drugs to target the population of cancer cells expressing stem cell markers.

• Authors: Elaine Langenfeld, Malik Deen, Emmanuel Zachariah, John Langenfeld
• Journal: Molecular cancer (Mol Cancer) Vol. 12 Issue 1 Pg. 129 (Oct 26 2013) ISSN: 1476-4598 [Electronic] England
• PMID: 24160469 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Nuclear
• Antineoplastic Agents
• Biomarkers, Tumor
• ID1 protein, human
• Inhibitor of Differentiation Protein 1
• Inhibitor of Differentiation Proteins
• NES protein, human
• Neoplasm Proteins
• Nerve Tissue Proteins
• Nestin
• Octamer Transcription Factor-3
• POU5F1 protein, human
• neuronal nuclear antigen NeuN, human
• ID3 protein, human
• Bone Morphogenetic Protein Receptors, Type I

Topics

• Animals
• Antigens, Nuclear (metabolism)
• Antineoplastic Agents (pharmacology)
• Biomarkers, Tumor (genetics, metabolism)
• Bone Morphogenetic Protein Receptors, Type I (antagonists & inhibitors, metabolism)
• Carcinoma, Non-Small-Cell Lung (metabolism)
• Cell Line, Tumor
• Humans
• Inhibitor of Differentiation Protein 1 (genetics, metabolism)
• Inhibitor of Differentiation Proteins (genetics, metabolism)
• Lung Neoplasms (metabolism)
• Mice
• Mice, Nude
• Neoplasm Proteins (genetics, metabolism)
• Neoplasm Transplantation
• Neoplastic Stem Cells (drug effects, metabolism)
• Nerve Tissue Proteins (metabolism)
• Nestin (metabolism)
• Octamer Transcription Factor-3 (metabolism)
• Signal Transduction
• Transcriptome (drug effects)