Khan S H, Sorof S
Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, PA 19111.
Proc Natl Acad Sci U S A. 1994 Feb 1;91(3):848-52. doi: 10.1073/pnas.91.3.848.
Peroxisome proliferators (PP) are a diverse group of chemicals that induce dramatic increases in peroxisomes in rodent hepatocytes, followed by hypertrophy, hepatomegaly, alterations in lipid metabolism, mitogenesis, and finally hepatocarcinomas. Termed nongenotoxic carcinogens, they do not interact with DNA, are not mutagenic in bacterial assays, and fail to elicit many of the phenotypes associated with classic genotoxic carcinogens. We report here that the mitogenesis induced by the major PP class, the amphipathic carboxylates, and by the tetrazole-substituted acetophenones specifically requires liver fatty acid-binding protein (L-FABP) in cultured rat hepatoma cells transfected with the sense cDNA of L-FABP, in contrast to L-FABP-nonexpressing cells transfected with its antisense cDNA. The mitogenic actions of L-FABP were protein-specific, inasmuch as no other protein in the nonexpressing cells could act like L-FABP. L-FABP was previously shown not only (i) to interact covalently with metabolites of the two genotoxic carcinogens 2-acetylaminofluorene and aminoazo dyes during liver carcinogenesis, but also (ii) to bind noncovalently the two classes of PP in vitro with avidities that correlate with their abilities to elicit peroxisomal enzymatic responses, and (iii) together with unsaturated fatty acids, especially linoleic acid, to promote multiplication of the transfected hepatoma cells in culture. The convergence of the two types of genotoxic carcinogens with the two classes of PP nongenotoxic carcinogens, and also with unsaturated fatty acids, at L-FABP actions in inducing mitogenesis allows the following hypothesis. During tumor promotion of carcinogenesis in vivo, these groups of genotoxic and nongenotoxic carcinogens act on the normal process by which L-FABP, functioning as a specific receptor of unsaturated fatty acids or their metabolites, promotes hepatocyte proliferation.
过氧化物酶体增殖剂（PP）是一类多样的化学物质，可使啮齿动物肝细胞中的过氧化物酶体显著增加，随后出现肥大、肝肿大、脂质代谢改变、有丝分裂，最终导致肝癌。它们被称为非遗传毒性致癌物，不与DNA相互作用，在细菌试验中无致突变性，也不会引发许多与经典遗传毒性致癌物相关的表型。我们在此报告，主要的PP类别（两亲性羧酸盐）和四唑取代的苯乙酮诱导的有丝分裂，在转染了L-FABP（肝脏脂肪酸结合蛋白）正义cDNA的培养大鼠肝癌细胞中特别需要L-FABP，这与转染了其反义cDNA的不表达L-FABP的细胞形成对比。L-FABP的促有丝分裂作用具有蛋白质特异性，因为在不表达的细胞中没有其他蛋白质能像L-FABP那样发挥作用。先前已表明，L-FABP不仅（i）在肝癌发生过程中与两种遗传毒性致癌物2-乙酰氨基芴和氨基偶氮染料的代谢产物共价相互作用，而且（ii）在体外以与其引发过氧化物酶体酶反应能力相关的亲和力非共价结合这两类PP，以及（iii）与不饱和脂肪酸，特别是亚油酸一起，促进培养中转染的肝癌细胞增殖。两种类型的遗传毒性致癌物与两类PP非遗传毒性致癌物以及不饱和脂肪酸在L-FABP诱导有丝分裂的作用上的汇聚，提出了以下假设。在体内致癌作用的肿瘤促进阶段，这些遗传毒性和非遗传毒性致癌物组作用于正常过程，在此过程中，L-FABP作为不饱和脂肪酸或其代谢产物的特异性受体，促进肝细胞增殖。
