EFFECT OF VARIOUS LYSOSOMOTROPIC AGENTS AND MICROTUBULE DISRUPTING DRUGS ON THE LACTOGENIC AND THE MAMMOGENIC ACTION OF PROLACTIN

Abstract

Various drugs added to the culture medium of rabbit mammary gland were assayed for their capacity to affect the lactogenic and the mammogenic activities of prolactin. Three lysosomotropic agents NH4Cl, chloroquine and methylamine which inhibit the degradation of the hormone-receptor complex after its internalization (down-regulation) did not prevent the initiation of casein synthesis, lactose synthetase activity and DNA synthesis. Five microtubule disrupting drugs, colchicine, colcemid, vinblastine, podophyllotoxin and nocodazole inhibited the induction of casein and DNA synthesis by prolactin; 2 inactive analogs, trimethylcholchicine acid and lumicolchicine had no effect. None of these drugs exhibited any general cytotoxic effect as judged by the capacity of the tissue to incorporate 14C amino acids into total proteins and 3H-uridine into total RNA. The microtubule disrupting drugs did not greatly reduce the rate of casein synthesis in the cultured mammary tissue explanted from lactating rabbits. Apparently the down-regulation of prolactin receptor is not strictly required for the 2 considered prolactin activities. The integrity of microtubules, or at least of structures in which tubulin is involved, is necessary to ensure a normal transmission of the prolactin information responsible for the initiation of milk and DNA synthesis. Because the lactogenic and mammogenic activities of prolactin are affected by the same drugs, these 2 properties of the hormone may be mediated by cellular mechanisms which have at least 1 common step.