Mechanism of induced resistance to protein inhibitors of proliferation.

A 12 kD protein (IHP-12) was isolated from the cytosol of liver cells; IHP-12 inhibited proliferation of the liver cells by 50% when injected at 2.5 mg/100 g animal weight. Repeated injections of IHP-12 induced resistance of the liver cells to its anti-proliferative effect. After intraperitoneal injection, IHP-12 is localized in the cytosol and to a lesser extent, in cell nuclei. IHP-12 is degraded in the cytosol but in nuclei it retained its native structure for at least 8 h. The mechanism of induced resistance to IHP-12 was not related to a change in cell binding of IHP-12, its distribution in cellular compartments, and intracellular metabolism. The induced resistance may be associated with a change in the direction of IHP-12 activity, i.e., change in its function in the animal.