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

Dai, W., Bai, Y., Hebda, L., Zhong, X., Liu, J., Kao, J., and Duan, C.
Cell death and differentiation   21(4): 568-81 (Journal)
Registered Authors
Duan, Cunming
MeSH Terms
  • Animals
  • Caco-2 Cells
  • Calcium/pharmacology*
  • Cell Proliferation/drug effects
  • Epithelial Cells/cytology
  • Epithelial Cells/drug effects
  • Epithelial Cells/metabolism*
  • Humans
  • Insulin-Like Growth Factor I/pharmacology
  • Insulin-Like Growth Factor II/pharmacology
  • Larva/cytology
  • Oligonucleotides, Antisense/metabolism
  • Phosphatidylinositol 3-Kinase/antagonists & inhibitors
  • Phosphatidylinositol 3-Kinase/genetics
  • Phosphatidylinositol 3-Kinase/metabolism
  • 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
  • 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*
24336047 Full text @ Cell Death Differ.

Calcium deficiency causes abnormal colonic growth and increases colon cancer risk with poorly understood mechanisms. Here we elucidate a novel signaling mechanism underlying the Ca2+ deficiency-induced epithelial proliferation using a unique animal model. The zebrafish larval yolk sac skin contains a group of Ca2+-transporting epithelial cells known as ionocytes. Their number and density increases dramatically when acclimated to low >[Ca2+] environments. BrdU pulse-labeling experiments suggest that low [Ca2+] stimulates pre-existing ionocytes to re-enter the cell cycle. Low [Ca2+] 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 Ca2+-selective channel Trpv5/6. Inhibition or knockdown of Igfbp5a, IGF1 receptor, PI3K, and Akt attenuates low [Ca2+]-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 [Ca2+]. These increases are eliminated in the presence of an IGF1R inhibitor, suggesting that Trpv5/6 represses IGF1R-PI3K-Akt signaling under normal [Ca2+]. Intriguingly, blockade of Trpv5/6 activity inhibits the low [Ca2+]-induced activation of Akt. Mechanistic analyses reveal that the low [Ca2+]-induced IGF signaling is mediated through Trpv5/6-associated membrane depolarization. Low extracellular [Ca2+] 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 Ca2>+ deficiency.

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