Abstract 3078: The fer/FerT cell survival pathway of the ancestral sponge (<i>Sycon raphanus</i>) becomes a mitochondrial proto-oncogene in the human genome
Authors: Joseph G. Sinkovics
Journal: Cancer Research (2018)

Abstract The Fer/FerT (truncated) genes and their encoded 879 aa / 100 kDa proteins (fujinami poultry sarcoma; feline sarcoma-related kinases) were discovered in the sponge Sycon raphanus [1]. The recognition of other related genes and their protein products (ras/RAS; src/SRC; the human Bruton kinase-related Tec family proteins, etc) in the descendants of ancestral sponges (Suberites; Spongilla) rapidly followed [1]. Primordial cell survival pathways were essential for the life style of early diploblastic multicellular eukaryotes (ctenophores; cnidarians; ciona, etc) in the hostile environment of the ancient Earth [2]. These preserved ancient cell survival pathways evolved into proto-oncogenes in triploblastic hosts (Homo), in order to allow switching back to them under circumstances of life-threatening intrusions, and in chronic infections of the inflammasomes [2]. The Author refers to this inherent fundamental biological principle as “retrograde cellular immortalization” [2]. A common form of this process is recognized in medical clinics as 'cancer' [2]. Constitutively up-regulated Fer/FerT genes and proteins redirect sugar metabolism toward Warburg's aerobic glycolysis with reduced Oxphosph (for ATP production) and tricarboxylic acid cycles. Downregulation of Fer/FerT results in a non-functional ETC. Tumor cells with nonfunctional mitochondrial ETC undergo either mTOR-directed autophagy, and/or necrotic death promoted by poly ADP-ribose polymerase (PARP-1) [3]. The novel inhibitor E260 of enzyme-like activity to Fer/FerT-induced kinases, attacks selectively mitochondrial (or cytoplasmic) Fer/FerT proteins. E260-treated cancer cells lose their ATP content and increase their glycolytic activity (especially in high glucose concentration), thus delaying (but not canceling) their death. These cancer cells operate with low hexokinase II levels and deregulated PARP-1. ATP-deficient cells activate AMPK, de-activate mTOR, and fail to recover from the state of autophagy, resulting in necrosis. So far, all healthy cells remained intact upon exposure to E260 [4]. Recalled ancient cell survival pathways operate as "protooncogenes-to-oncoproteins" in extant triploblastic hosts [2]. References 1. Ćetković H et al Gene 1998;216(1):77-84; Genomics 2004;83(4):743-745. 2. Sinkovics J G RNA/DNA &amp; Cancer. Springer Verlag 2016 ERRATA in Author's CV; Int J Oncol 2015;47:1211-1229 ERRATUM Hydra viridis viridissima DOI: 10.3892/ijo.2016.3762 IJO 2017;50(1):338; Int J Oncol 2012;40:305-349; Inverteb Surviv J 2016;13:68-75 ERRATUM A. japonicus 3. Yaffe E et al Cancer Res 2014;74(22):6474-85. 4. Elkis Y et al Nature Commun 2017;8:940 DOI: 10.1038/s41467-017-00832-W. Citation Format: Joseph G. Sinkovics. The fer/FerT cell survival pathway of the ancestral sponge (Sycon raphanus) becomes a mitochondrial proto-oncogene in the human genome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3078.