Konger R L, Chan T C
Department of Physiology and Pharmacology, School of Veterinary Medicine, Purdue University, West Lafayette, Indiana 47907.
J Cell Physiol. 1993 Sep;156(3):515-21. doi: 10.1002/jcp.1041560310.
Previous studies have reported that the proliferation of A431 cells, a human squamous cell carcinoma cell line, was stimulated by picomolar epidermal growth factor (EGF) but inhibited by nanomolar EGF. This biphasic dose-response phenomenon is not observed in normal human epithelial cells where nanomolar EGF is usually mitogenic. We have examined the effects of inhibitory and stimulatory concentrations of EGF on the growth and differentiation of A431 cells. In the presence of 100 pM EGF, A431 cells showed a mild increase in growth rate (129% of control) compared to cells grown in the absence of EGF. At 10 nM EGF, growth inhibition to 63% of control was observed. EGF at 10 nM stimulates a twofold increase both in cornified envelope formation and in epidermal transglutaminase activity, suggesting that high concentrations of EGF induce terminal differentiation in A431 cells. Mitogenic concentrations of EGF (100 pM) had no significant effect on these differentiation markers. Chronic exposure of A431 cells to 20 or 50 nM EGF resulted in EGF-resistant A431 variants that are neither growth arrested nor induced to terminally differentiate by 10 nM EGF. Removal of EGF from the growth medium of the EGF-resistant cells resulted in the reversion of these cells back to the wild-type A431 biphasic response pattern within 2 weeks. Our results suggest that A431 cells have the capacity to non-mutatively alter their response pattern to EGF in vitro to maintain themselves in a state of optimum proliferation and away from terminal differentiation.
先前的研究报道，人鳞状细胞癌细胞系A431细胞的增殖受到皮摩尔浓度表皮生长因子（EGF）的刺激，但受到纳摩尔浓度EGF的抑制。在正常人上皮细胞中未观察到这种双相剂量反应现象，在正常人上皮细胞中纳摩尔浓度的EGF通常具有促有丝分裂作用。我们研究了抑制性和刺激性浓度的EGF对A431细胞生长和分化的影响。在存在100 pM EGF的情况下，与在无EGF条件下生长的细胞相比，A431细胞的生长速率略有增加（为对照的129%）。在10 nM EGF时，观察到生长抑制至对照的63%。10 nM的EGF刺激角质化包膜形成和表皮转谷氨酰胺酶活性增加两倍，表明高浓度的EGF诱导A431细胞终末分化。有丝分裂浓度的EGF（100 pM）对这些分化标志物没有显著影响。将A431细胞长期暴露于20或50 nM EGF会产生对EGF耐药的A431变体，这些变体既不会因10 nM EGF而生长停滞，也不会被诱导终末分化。从耐EGF细胞的生长培养基中去除EGF会导致这些细胞在2周内恢复为野生型A431双相反应模式。我们的结果表明，A431细胞有能力在体外非突变地改变其对EGF的反应模式，以维持自身处于最佳增殖状态并远离终末分化。
