Nonsecreted cytoplasmic alpha-fetoprotein: a newly discovered role in intracellular signaling and regulation. An update and commentary
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The concept of a non-secreted cytoplasmic-bound form of alpha-fetoprotein is not a new notion in AFP biological activities. Cytoplasmic AFP (CyAFP) is a long known but forgotten protein in search of a function other than a histochemical biomarker. In this report, CyAFP is presented as an “old” protein with a newly described intracellular function. In 1976, CyAFP was shown to be a product of hepatoma cells utilizing 14Cleucine incorporation and demonstrated by autoradiographic procedures. The synthesis of CyAFP without secretion was demonstrated to occur in both malignant and non-malignant cells encompassing hepatomas, ascite fluid cells, immature rodent uterus, MCF-7 breast cancers, and cytosols from human breast cancer patients. Using computer protein matching and alignments in AFP versus members of the nuclear receptor superfamily, a consecutive series of leucine zipper (heptad) repeats in AFP was previously reported, suggesting the possibility for protein-to-protein interactions. The potential for heptad heterodimerization between protein-binding partners provided the rationale for proposing that CyAFP might have the capability to form molecular hetero-complexes with cytoplasmic based transcription factors. More recent investigations have now provided experimental evidence that CyAFP is capable of colocalizing and interacting with transcription-associated factors. Such proteins can modulate intracellular signaling leading to regulation of transcription factors and initiation of growth in human cancer cells. Although circulating serum AFP is known as a growth-enhancing factor during development, cytoplasmic AFP has a lethal role in the oncogenesis, growth, and metastasis of adult liver cancer.
KeywordsAlpha-fetoprotein Caspase-3 PI3K/AKT Retinoic acid receptor PTEN GADD153 Dimerization Heptad repeats
The author wishes to extend his thanks and gratitude to Ms. Tracy Godfrey for the typing and processing of this manuscript. The author also wishes to dedicate this paper to the memory of Dr. Edward J. Sarcione for his 1976 discovery of cytoplasmic alpha-fetoprotein.
Conflicts of interest
- 1.Mizejewski GJ. Alpha-fetoprotein structure and function: Relevance to isoforms, epitopes, and conformational variants. Exp Biol Med. 2001;226:377–408.Google Scholar
- 2.Mizejewski GJ. Biological roles of alpha-fetoprotein during pregnancy and perinatal development. Exp Biol Med. 2004;229:439–63.Google Scholar
- 5.Sell S. Heterogeneity of alpha-fetoprotein (afp) and albumin containing cells in normal and pathological permissive states for afp production: Afp containing cells induced in adult rats recapitulate the appearance of afp containing hepatocytes in fetal rats. Onco Dev Biol Med. 1980;1:93–105.Google Scholar
- 30.Petropoulos CJ, Yaswen P, Panzica M, Fausto N. Cell lineages in liver carcinogenesis: possible clues from studies of the distribution of alpha-fetoprotein rna sequences in cell populations isolated from normal, regenerating, and preneoplastic rat livers. Cancer Res. 1985;45:5762–8.PubMedGoogle Scholar
- 33.Morinaga T, Sakai M, Wegmann TG, Tamaoki T. Alphafetoprotein messenger rna in human embryonal carcinoma grown in nude mice, and cloning of its complementary DNA. Onco Dev Biol Med. 1982;3:301–13.Google Scholar
- 41.Li MS, Ma QL, Chen Q, Liu XH, Li PF, Du GG, et al. Alpha-fetoprotein triggers hepatoma cells escaping from immune surveillance through altering the expression of fas/fasl and tumor necrosis factor related apoptosis-inducing ligand and its receptor of lymphocytes and liver cancer cells. World J Gastroenterol. 2005;11:2564–9.CrossRefPubMedPubMedCentralGoogle Scholar
- 47.Lin YS, Zhu MY, Zhou S, Xie XJ, Li MS. [effects of alpha-fetoprotein on the expression of trail death receptor-2 and its role on resisting the cytotoxicity of trail in hepatoma cells]. Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi =. Chin J Hepatol. 2010;18:745–50.Google Scholar
- 49.Zhu MY, Guo JL, Xia H, Li W, Lu Y, Dong X, et al. [the anti-apoptotic effect of cytoplasmic alpha-fetoprotein in hepatoma cells induced by all-trans retinoic acid involves activation of the pi3k/akt signaling pathway]. Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi =. Chin J Hepatol. 2014;22:837–42.Google Scholar
- 58.Zhang C, Chen X, Liu H, Li H, Jiang W, Hou W, et al. Alpha fetoprotein mediates hbx induced carcinogenesis in the hepatocyte cytoplasm. Int J Cancer. 2015;4.Google Scholar
- 60.Mizejewski GJ. The alpha-fetoprotein third domain receptor binding fragment: in search of scavenger and associated receptor targets. J Drug Target. 2015;13:1–14.Google Scholar