PubMed · 5023907
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1972-05-13. Differences in thyroid cancer.. https://pubmed.ncbi.nlm.nih.gov/5023907/
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The G12 subfamily of heterotrimeric G proteins, comprised of the alpha-subunits Galpha12 and Galpha13, has been implicated as a signaling component in cellular processes ranging from cytoskeletal changes to cell growth and oncogenesis. In an attempt to elucidate specific roles of this subfamily in cell regulation, we sought to identify molecular targets of Galpha12. Here we show a specific interaction between the G12 subfamily and the cytoplasmic tails of several members of the cadherin family of cell-surface adhesion proteins. Galpha12 or Galpha13 binding causes dissociation of the transcriptional activator beta-catenin from cadherins. Furthermore, in cells lacking the adenomatous polyposis coli protein required for beta-catenin degradation, expression of mutationally activated Galpha12 or Galpha13 causes an increase in beta-catenin-mediated transcriptional activation. These findings provide a potential molecular mechanism for the previously reported cellular transforming ability of the G12 subfamily and reveal a link between heterotrimeric G proteins and cellular processes controlling growth and differentiation.
Interleukin-2 (IL-2) has been shown to decrease cytochrome P450 (CYP) mRNAs and proteins in cultured rat hepatocytes, and IL-2 administration decreases CYPs in rats. Although high doses of IL-2 are administered to cancer patients, the effect on human CYPs has not yet been determined. Patients with hepatic metastases from colon or rectum carcinomas were randomly allocated to various daily doses of human recombinant IL-2 (from 0 to 12.10(6) units/m(2)). IL-2 was infused from day 7 to day 3 before hepatectomy and the conservation of a non-tumorous liver fragment in liquid nitrogen. Hepatic CYPs and monooxygenase activities were not significantly decreased in 5 patients receiving daily doses of 3 or 6 10(6) IL-2 units/m2, compared to 7 patients who did not receive IL-2. In contrast, in 6 patients receiving daily doses of 9 or 12 x 10(6) IL-2 units/m2, the mean values for immunoreactive CYP1A2, CYP2C, CYP2E1, and CYP3A4 were 37, 45, 60 and 39%, respectively, of those in controls; total CYP was significantly decreased by 34%, methoxyresorufin O-demethylation by 62%, and erythromycin N-demethylation by 50%. These observations suggest that high doses of IL-2 may decrease total CYP and monooxygenase activities in man.
Retinoids are natural differentiation-inducing compounds that are promising as anticancer agents. Cancer cell lines are valuable in the investigation of the potential of retinoids for the treatment of specific cancers. However, using different treatment conditions but the same cell lines, investigators have produced markedly contradictory results for the effectiveness of retinoids. The present study examined different factors in the treatment conditions that may have masked or interfered with the effects of retinoids and, thereby, resulted in this conflict. Our studies revealed that the effects of retinoids on cancer cell proliferation were influenced by serum, the choice of vehicle (DMSO vs ethanol) and its concentration, phenol red, the degree of cellular confluence, and the method of assessing proliferation (cell number or [3H]thymidine uptake vs the MTT assay). Optimized conditions were the use of serum-free, ethanol-free, and phenol red-free media, investigating cells in the log phase of growth, using </=0.01% DMSO as the vehicle, and monitoring proliferation by cell number or [3H]thymidine incorporation into DNA measured after TCA precipitation. Using these conditions, retinoids were found to exhibit potent antiproliferative effects in pancreatic cancer cells with a variety of degrees of differentiation, even in cell lines previously documented as being retinoid resistant. Retinoids also induced morphological changes and cellular death that may indicate terminal differentiation and apoptosis.