title: Role of the endocytic pathway in carcinogenesis.
abstract: This commentary was prompted by many reports that carcinogenesis involving various carcinogens and various types of systems is blocked by inhibitors of endolysosomal proteases (i.e. leupeptin, antipain). These findings have been largely ignored by cancer investigators so far. In this commentary based on these reports a carcinogenesis model is suggested that does not involve direct attack by the carcinogen onto target cell DNA. This model proposes the following steps in the initial phase of carcinogenesis: interaction of a carcinogen with an appropriate cell surface receptor (i.e. possibly the receptor for the epidermal growth factor). This carcinogen–receptor complex is endocytosed and fragmented by various cathepsins to form small peptides (i.e. di-and tripeptides) some of which enter the nucleus and interact very specifically with the protein repressors that normally (during G0 phase) inhibit expression of oncogenes critical to the transformation process. This interaction causes removal of the repressors from these oncogenes. The oncogenes, freed from their repressors are then expressed, culminating in carcinogenesis. This then defines the G0/G1 transition comprising the initial phases of carcinogenesis. Note is taken of reports that the only cells transformed in a heterogeneous collection of cells comprising target organs are in the G0 stem cell subpopulation. The need for such an alternative mechanism is outlined in terms of reports that major kinases (i.e. MAPK and PI3K) operate only after entry into cell cycle (during G1). Thus an answer is provided as to what events occur before entry into cell cycle, the events that define the transition from G0 to G1. In addition, note it taken of the recent reports that suggest that epigenetic mechanisms operate in the carcinogenic process and an attempt is made to harmonize the model presented in this commentary with epigenetic mechanisms as proposed in recent years.
authors.affiliation: msmelzer16@hotmail.com
authors.forename: Marvin S
authors.initials: MS
authors.lastname: Melzer
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D004247:DNA / Q000096:biosynthesis / Q000235:genetics; D004705:Endocytosis / Q000502:physiology*; D057890:Epigenomics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008247:Lysosomes / Q000187:drug effects; D015233:Models, Statistical; D009369:Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D010447:Peptide Hydrolases / Q000378:metabolism; D010455:Peptides / Q000235:genetics
chemical_list: D002273:Carcinogens; D010455:Peptides; D004247:DNA; D010447:Peptide Hydrolases