Calcium deficiency-induced and TRP channel-regulated IGF1R-PI3K-Akt signaling regulates abnormal epithelial cell proliferation

• Published in: Cell death and differentiation Vol. 21; no. 4; pp. 568 - 581
• Main Authors: Dai, W, Bai, Y, Hebda, L, Zhong, X, Liu, J, Kao, J, Duan, C
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-04-2014; Nature Publishing Group
• Subjects: 631/136/2091; 631/67/1504/1885/1393; 631/80/86/1999; Animals; Apoptosis; Biochemistry; Biomedical and Life Sciences; Caco-2 Cells; Calcium - pharmacology; Cell Biology; Cell cycle; Cell Cycle Analysis; Cell death; Cell growth; Cell Proliferation - drug effects; Colorectal cancer; Danio rerio; Developmental biology; Embryos; Epithelial Cells - cytology; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Humans; Insulin; Insulin-Like Growth Factor I - pharmacology; Insulin-Like Growth Factor II - pharmacology; Insulin-like growth factors; Larva - cytology; Life Sciences; Oligonucleotides, Antisense - metabolism; Original Paper; Phosphatidylinositol 3-Kinase - antagonists & inhibitors; Phosphatidylinositol 3-Kinase - genetics; Phosphatidylinositol 3-Kinase - metabolism; Proteins; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Receptor, IGF Type 1 - antagonists & inhibitors; Receptor, IGF Type 1 - genetics; Receptor, IGF Type 1 - metabolism; Signal Transduction - drug effects; Sodium-Potassium-Exchanging ATPase - metabolism; Stem Cells; TRPV Cation Channels - antagonists & inhibitors; TRPV Cation Channels - genetics; TRPV Cation Channels - metabolism; Yolk Sac - cytology; Zebrafish - growth & development; Zebrafish - metabolism; Zebrafish Proteins - antagonists & inhibitors; Zebrafish Proteins - genetics; Zebrafish Proteins - metabolism; Ann Arbor Michigan; United States > US; China; insulin-like growth factor binding protein 5; transient receptor potential vanilloid; zebrafish; colon cancer cell; epithelial growth; membrane depolarization
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2013.177

Calcium deficiency causes abnormal colonic growth and increases colon cancer risk with poorly understood mechanisms. Here we elucidate a novel signaling mechanism underlying the Ca
2+
deficiency-induced epithelial proliferation using a unique animal model. The zebrafish larval yolk sac skin contains a group of Ca
2+
-transporting epithelial cells known as ionocytes. Their number and density increases dramatically when acclimated to low [Ca
2+
] environments. BrdU pulse-labeling experiments suggest that low [Ca
2+
] stimulates pre-existing ionocytes to re-enter the cell cycle. Low [Ca
2+
] treatment results in a robust and sustained activation of IGF1R-PI3K-Akt signaling in these cells exclusively. These ionocytes specifically express Igfbp5a, a high-affinity and specific binding protein for insulin-like growth factors (IGFs) and the Ca
2+
-selective channel Trpv5/6. Inhibition or knockdown of Igfbp5a, IGF1 receptor, PI3K, and Akt attenuates low [Ca
2+
]-induced ionocyte proliferation. The role of Trpv5/6 was investigated using a genetic mutant, targeted knockdown, and pharmacological inhibition. Loss-of-Trpv5/6 function or expression results in elevated pAkt levels and increased ionocyte proliferation under normal [Ca
2+
]. These increases are eliminated in the presence of an IGF1R inhibitor, suggesting that Trpv5/6 represses IGF1R-PI3K-Akt signaling under normal [Ca
2+
]. Intriguingly, blockade of Trpv5/6 activity inhibits the low [Ca
2+
]-induced activation of Akt. Mechanistic analyses reveal that the low [Ca
2+
]-induced IGF signaling is mediated through Trpv5/6-associated membrane depolarization. Low extracellular [Ca
2+
] results in a similar amplification of IGF-induced PI3K-PDK1-Akt signaling in human colon cancer cells in a TRPV6-dependent manner. These results uncover a novel and evolutionarily conserved signaling mechanism that contributes to the abnormal epithelial proliferation associated with Ca
2+
deficiency.