Abstract C97: Studies on the signaling pathway for cancer cell migration based on chemical genomic approach.

Abstract

Abstract Cell migration is known to be related to not only physiological phenomena such as embryonic development, immune reaction, and wound healing, but also pathological phenomena such as asthma, vascular disease, and cancer metastasis. However, because genetic mutations of each cancer cell causing high migration ability depend on cell types, it still remains unclear that which pathways are the unity of cancer cell migration signaling irrespective of cancer cell types, and which pathways are the diversity depend on cell types. The aim of this study is to reveal the diversity and unity of regulatory signaling for cancer cell migration based on chemical genomic approach. To understand the diversity and unity of regulatory signaling for cancer cell migration, the effects of 38 small compounds, whose target protein are already identified, on cell migration ability of 10 types of cancer cells were assessed quantitatively by wound healing assay. Two-way hierarchical clustering was done on migration ability profile by small compounds or cancer cell types. As a result, cancer cells tested in this study were classified into three clusters (group A∼C). Interestingly, epidermoid carcinoma A431 cells and esophageal squamous carcinoma EC109 cells (group B) were classified different cluster from esophageal squamous carcinoma TE8 cells and thyroid medullary carcinoma T.T cells (group C), whereas all four cell lines were induced migration by EGF stimulation. On the other hand, compounds were clustered into five clusters (cluster I∼V). The compounds classified into cluster I (e.g., V-ATPase inhibitor and bisphosphonates) showed little inhibitory effect on all types of cell migration. The compounds clustered into cluster II (e.g., EGFR inhibitor and ROCK inhibitor) showed stronger inhibitory effect on the migration of group B and C than A. The compounds classified into cluster III (e.g., JNK inhibitor) showed strong inhibitory effect on all types of cell migration tested in this study. The compounds clustered into cluster IV (e.g., PI3K inhibitors and mTOR inhibitor) showed stronger inhibitory effect on the migration of group B than C. On the contrary, the compounds classified into cluster V (e.g., MEK inhibitor and p38 inhibitors) showed stronger inhibitory effect on group C than B. These results indicate that JNK play the common role in cancer cell migration, and belonging to cluster II, IV, and V would have different function in each type of cancer cell migration. We are now investigating how these molecules actually operate in the signaling pathway in each cancer cell, and trying network analysis by the combination of chemical biology and systems biology. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C97.