Alterations in receptor-mediated kinases and phosphatases during carcinogenesis

David H. Crean, Charles Liebow, Ming Ting Lee, Angela R. Kamer, Andrew V. Schally, Thomas S. Mang

Research output: Contribution to journalArticlepeer-review

Abstract

Increased phosphorylation in cancers can stimulate growth and up-regulate certain receptors. To test whether the functional response of phosphatase receptors is up-regulated during carcinogenesis, we examined the effects of ligands on net phosphorylation in isolated membranes derived from hamster cheekpouch tissues undergoing malignant transformation. The buccal mucosa of groups of Syrian golden hamsters was exposed thrice weekly to 0.5% dimethylbenzanthracene (DMBA) in acetone for 2-12 weeks to produce premalignant and malignant tissues. Homogenates of these tissues were then incubated with [32P]ATP in the presence of epidermal growth factor (EGF), agonist of somatostatin analogue RC-160, luteinizing-hormone-releasing hormone (LH-RH) [d-Trp6]LH-RH, or combinations of EGF, RC-160, and [d-Trp6]LH-RH. Changes compared to controls in phosphorylation in response to ligands provided estimates of kinase or phosphatase activity. Phosphorylation increased continuously, from the first application of DMBA in a linear fashion, and independently of EGF stimulation. RC-160 and [d-Trp6]LH-RH reduced phosphorylation in vitro. This response occurred in premalignant (weeks 6-10 after DMBA application) as well as malignant tissues (week 12 after DMBA application), but was not significant in normal tissues. The results show a continuous augmentation in phosphatase activity prior to the appearance of cancers, but with a delay in expression following the primary event of increased kinase activity. Significantly less phosphorylation of substrates was induced by both RC-160 and [d-Trp6]LH-RH after in vitro activation by EGF than in the absence of EGF. This suggests that EGF activates latent systems of hormonal receptors. Collectively, these results support the hypothesis that the enhancement of the hormonally stimulated phosphatase in cancers occurs secondarily to the increased kinase activity.

Original languageEnglish (US)
Pages (from-to)141-149
Number of pages9
JournalJournal of Cancer Research and Clinical Oncology
Volume121
Issue number3
DOIs
StatePublished - Mar 1995

Keywords

  • Luteinizing-hormone-releasing hormone [D-Trp]LH-RH
  • Receptor kinases
  • Receptor phosphatases
  • Somatostatin analogue RC-160

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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