Buckley A R, Putnam C W, Russell D H
Department of Pharmacology, University of Arizona College of Medicine, Tucson 85724.
Adv Enzyme Regul. 1988;27:371-91. doi: 10.1016/0065-2571(88)90027-1.
Cellular proliferation and differentiation of the mammalian mammary gland requires a medley of hormones including the anterior pituitary hormone, PRL. Recent evidence extends the role of PRL as a mammalian mitogen to cells in several physiological systems not directly involved in reproductive functions, such as liver and lymphocytes. PRL administration induces biochemical markers expressed during the G1 phase of cell cycle and activates DNA synthesis in rat liver. Chronic PRL treatment causes hepatomegaly, reflecting its stimulation of the proliferative process. In vitro, a lactogen-dependent cell line, the Nb2 rat node lymphoma cell, serves as a useful paradigm to study PRL action on mitogenesis. These cells, when cultured in the presence of lactogens, proliferate in a dose-dependent manner. The effects of various pharmacological agents on discrete phases of the cell cycle may be readily assessed in these cells since PRL-stimulated entry into cycle is signalled by an elevation of ODC activity at 6 hr and entry into S-phase at 6-12 hr. The parallel effects of phorbol ester tumor promoters and PRL on cell cycle progression in Nb2 lymphoma cells and in hepatic proliferation suggest that PRL may likewise mediate proliferation in aberrant growth conditions such as neoplasia. The data presented support the hypothesis that PRL is capable of promoting hepatocarcinogenesis. Its chronic administration after a hepatic initiating agent stimulated the development of histochemical and biochemical markers characteristic of preneoplasia. Further, the effect of PRL was comparable to that of the hepatocarcinogen when either was administered alone. Thus, hyperprolactinemia may serve to promote the development of hepatic tumors. Phorbol esters are thought to promote tumorigenesis by directly activating PKC. In the Nb2 lymphoma cell model, tumor promoting phorbol esters mimic the effects of PRL. Similarly, PRL-stimulated enzyme induction in liver is mirrored by phorbol ester treatment, and inhibitors of PKC block PRL-stimulated mitogenesis in Nb2 cells. Further, PRL or TPA administration to rats causes translocation of PKC activity from the hepatic cytosol to the membrane fraction, reflecting kinase activation. Therefore, PRL activation of PKC appears to be a physiological phenomenon of general significance, occurring as the result of lactogen receptor stimulation and serving to transmit intracellular signals linked to the regulation of mitogenesis. Further study is required to more fully define the scope of PRL-mediated mitogenic actions as well as its effects on the expression of differentiated products in tissues and cells.
哺乳动物乳腺的细胞增殖和分化需要多种激素，包括垂体前叶激素催乳素（PRL）。最近的证据表明，PRL作为一种哺乳动物有丝分裂原，其作用范围已扩展到一些与生殖功能无直接关联的生理系统中的细胞，如肝脏和淋巴细胞。给予PRL可诱导细胞周期G1期表达的生化标志物，并激活大鼠肝脏中的DNA合成。长期给予PRL会导致肝脏肿大，这反映了它对增殖过程的刺激作用。在体外，一种依赖催乳素的细胞系，即Nb2大鼠淋巴结淋巴瘤细胞，是研究PRL对有丝分裂作用的有用模型。这些细胞在催乳素存在的情况下培养时，会以剂量依赖的方式增殖。由于PRL刺激进入细胞周期是由6小时时鸟氨酸脱羧酶（ODC）活性升高以及6至12小时进入S期所标志的，因此在这些细胞中可以很容易地评估各种药理剂对细胞周期不同阶段的影响。佛波酯肿瘤促进剂和PRL对Nb2淋巴瘤细胞的细胞周期进程以及肝脏增殖的平行作用表明，PRL在诸如肿瘤形成等异常生长条件下可能同样介导细胞增殖。所呈现的数据支持PRL能够促进肝癌发生的假说。在给予肝脏起始剂后长期给予PRL会刺激癌前病变特征性的组织化学和生化标志物的发展。此外，单独给予PRL或肝癌致癌物时，其效果相当。因此，高催乳素血症可能有助于促进肝脏肿瘤的发展。佛波酯被认为通过直接激活蛋白激酶C（PKC）来促进肿瘤发生。在Nb2淋巴瘤细胞模型中，具有肿瘤促进作用的佛波酯模拟了PRL的作用。同样，佛波酯处理反映了PRL刺激肝脏中的酶诱导，并且PKC抑制剂可阻断PRL刺激的Nb2细胞有丝分裂。此外，给大鼠注射PRL或12-O-十四酰佛波醇-13-乙酸酯（TPA）会导致PKC活性从肝细胞溶质转移到膜部分，这反映了激酶的激活。因此，PRL对PKC的激活似乎是一种具有普遍意义的生理现象，它是由催乳素受体刺激导致的，并且用于传递与有丝分裂调节相关的细胞内信号。需要进一步研究以更全面地界定PRL介导的有丝分裂作用范围及其对组织和细胞中分化产物表达的影响。
