Inositol-C2-PAF acts as a biological response modifier and antagonizes cancer-relevant processes in mammary carcinoma cells.

Abstract

PURPOSE:

Previous studies have identified alkyl-phospholipids as promising compounds for cancer therapy by targeting constituents of the cell membrane and different signaling pathways. We previously showed that the alkylphospholipid Inositol-C2-PAF inhibits the proliferation and migration of immortalized keratinocytes and the squamous carcinoma-derived cell line SCC-25. Here, we investigated the effect of this compound on growth and motility as well as its mode of action in mammary carcinoma-derived cell lines.

METHODS:

Using BrdU incorporation and haptotactic cell migration assays, we assessed the effects of Inositol-C2-PAF on MCF-7 and MBA-MB-231 cell proliferation and migration. The phosphorylation status of signaling molecules was investigated by Western blotting as well as indirect immunofluorescence analysis and capillary isoelectric focusing.

RESULTS:

We found that Inositol-C2-PAF inhibited the growth as well as the migration in MCF-7 and MBA-MB-231 cells. Furthermore, we found that this compound inhibited phosphorylation of the protein kinase Akt at serine residue 473, but had no impact on phosphorylation at threonine 308. Phosphorylation of other kinases, such as Erk1/2, FAK and Src, which are targeted by Inositol-C2-PAF in other cells, remained unaffected by the compound in the mammary carcinoma-derived cell lines tested. In MCF-7 cells, we found that IGF-1-induced growth, as well as phosphorylation of AktS473, mTOR and the tumor suppressor pRB, was inhibited in the presence of Inositol-C2-PAF. Moreover, we found that in these cells IGF-1 had no impact on migration and did not seem to be linked to full Akt activity. Therefore, MCF-7 cell migration appears to be inhibited by Ino-C2-PAF in an Akt-independent manner.

CONCLUSION:

The antagonistic effects of Inositol-C2-PAF on cell migration and proliferation are indicative for its potential for breast cancer therapy, alone or in combination with other cytostatic drugs.

• Authors: Carsten Pelz, Sonja Häckel, Geo Semini, Sandra Schrötter, Willem Bintig, Sebastian Stricker, Gudrun Mrawietz, Andreas Klein, Lothar Lucka, Vadim Shmanai, Britta Eickholt, Annette Hildmann, Kerstin Danker
• Journal: Cellular oncology (Dordrecht) (Cell Oncol (Dordr)) Vol. 41 Issue 5 Pg. 505-516 (Oct 2018) ISSN: 2211-3436 [Electronic] Netherlands
• PMID: 30047091 (Publication Type: Journal Article)

Chemical References

• 1-O-octadecyl-2-O-(2-inositolylethyl)-glycero-3-phosphatidylcholine
• Antineoplastic Agents
• IGF1 protein, human
• Platelet Activating Factor
• Inositol
• Insulin-Like Growth Factor I

Topics

• Antineoplastic Agents (pharmacology)
• Breast Neoplasms (metabolism)
• Cell Line, Tumor
• Cell Movement (drug effects, genetics)
• Cell Proliferation (drug effects, genetics)
• Female
• Humans
• Inositol (analogs & derivatives, pharmacology)
• Insulin-Like Growth Factor I (genetics, metabolism)
• MCF-7 Cells
• Platelet Activating Factor (analogs & derivatives, pharmacology)
• Signal Transduction (drug effects, genetics)