Heptachlor epoxide induces a non-capacitative type of Ca2+ entry and immediate early gene expression in mouse hepatoma cells

Mark E. Hansen, Isaac N Pessah, Fumio Matsumura

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

The effects of the organochlorine (OC) liver tumor promoter heptachlor epoxide (HE) and a related non-tumor promoting OC, delta-hexachlorocyclohexane (δ-HCH), on the dynamics of intracellular calcium (Ca2+) were investigated in mouse 1c1c7 hepatoma cells. HE induced a non-capacitative, Ca2+ entry-like phenomenon, which was transient and concentration-dependent with 10 and 50 μM HE. The plasma membrane Ca 2+ channel blocker SKF-96365 antagonized this HE-induced Ca 2+ entry. δ-HCH failed to induce Ca2+ entry, rather it antagonized the HE-induced Ca2+ entry. Both HE and δ-HCH induced Ca2+ release from endoplasmic reticulum (ER) at treatment concentrations as low as 10 μM; at 50 μM, the former induced 5× as much Ca2+ release as the latter. The HE-induced Ca2+ release from the ER was antagonized using the IP3 receptor/channel blocker xestospongin C, suggesting that HE induces ER Ca2+ release through the IP3 receptor/channel pore. These results show that the effect of HE on cellular Ca2+ mimics that of mitogens such as epidermal and hepatocyte growth factors. They also provide insight into the similarities and differences between tumorigenic and non-tumorigenic OCs, in terms of the mechanisms and the extent of the [Ca2+]i increased by these agents.

Original languageEnglish (US)
Pages (from-to)218-231
Number of pages14
JournalToxicology
Volume220
Issue number2-3
DOIs
StatePublished - Mar 15 2006

Fingerprint

Heptachlor Epoxide
Immediate-Early Genes
Gene expression
Hepatocellular Carcinoma
Gene Expression
Endoplasmic Reticulum
Inositol 1,4,5-Trisphosphate Receptors
1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole
Hepatocyte Growth Factor
Cell membranes
Mitogens
Carcinogens
Liver
Hepatocytes
Cell Membrane

Keywords

  • Ca entry
  • Delta-HCH
  • Hepatoma cells
  • Heptachlor epoxide
  • Intracellular Ca
  • Liver cancer

ASJC Scopus subject areas

  • Toxicology

Cite this

Heptachlor epoxide induces a non-capacitative type of Ca2+ entry and immediate early gene expression in mouse hepatoma cells. / Hansen, Mark E.; Pessah, Isaac N; Matsumura, Fumio.

In: Toxicology, Vol. 220, No. 2-3, 15.03.2006, p. 218-231.

Research output: Contribution to journalArticle

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AB - The effects of the organochlorine (OC) liver tumor promoter heptachlor epoxide (HE) and a related non-tumor promoting OC, delta-hexachlorocyclohexane (δ-HCH), on the dynamics of intracellular calcium (Ca2+) were investigated in mouse 1c1c7 hepatoma cells. HE induced a non-capacitative, Ca2+ entry-like phenomenon, which was transient and concentration-dependent with 10 and 50 μM HE. The plasma membrane Ca 2+ channel blocker SKF-96365 antagonized this HE-induced Ca 2+ entry. δ-HCH failed to induce Ca2+ entry, rather it antagonized the HE-induced Ca2+ entry. Both HE and δ-HCH induced Ca2+ release from endoplasmic reticulum (ER) at treatment concentrations as low as 10 μM; at 50 μM, the former induced 5× as much Ca2+ release as the latter. The HE-induced Ca2+ release from the ER was antagonized using the IP3 receptor/channel blocker xestospongin C, suggesting that HE induces ER Ca2+ release through the IP3 receptor/channel pore. These results show that the effect of HE on cellular Ca2+ mimics that of mitogens such as epidermal and hepatocyte growth factors. They also provide insight into the similarities and differences between tumorigenic and non-tumorigenic OCs, in terms of the mechanisms and the extent of the [Ca2+]i increased by these agents.

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