title: Exosome-mediated delivery of the intrinsic C-terminus domain of PTEN protects it from proteasomal degradation and ablates tumorigenesis.
abstract: PTEN mutation is a frequent feature across a plethora of human cancers, the hot-spot being its C-terminus (PTEN-CT) regulatory domain resulting in a much diminished protein expression. In this study, the presence of C-terminus mutations was confirmed through sequencing of different human tumor samples. The kinase CKII-mediated phosphorylation of PTEN at these sites makes it a loopy structure competing with the E3 ligases for binding to its lipid anchoring C2 domain. Accordingly, it was found that PTEN-CT expressing stable cell lines could inhibit tumorigenesis in syngenic breast tumor models. Therefore, we designed a novel exosome-mediated delivery of the intrinsic PTEN domain, PTEN-CT into different cancer cells and observed reduced proliferation, migration, and colony forming ability. The delivery of exosome containing PTEN-CT to breast tumor mice model was found to result in significant regression in tumor size with the tumor sections showing increased apoptosis. Here, we also report for the first time an active PTEN when its C2 domain is bound by PTEN-CT, probably rendering its anti-tumorigenic activities through the protein phosphatase activity. Therefore, therapeutic interventions that focus on PTEN E3 ligase inhibition through exosome-mediated PTEN-CT delivery can be a probable route in treating cancers with low PTEN expression.
authors.affiliation: Signal Transduction in Cancer and Stem Cells Laboratory, Department of Cancer Biology and Inflammatory Disorder, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), Kolkata, West Bengal, India.
authors.forename: Syed Feroj
authors.initials: SF
authors.lastname: Ahmed
authors.affiliation: Signal Transduction in Cancer and Stem Cells Laboratory, Department of Cancer Biology and Inflammatory Disorder, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), Kolkata, West Bengal, India.
authors.forename: Nilanjana
authors.initials: N
authors.lastname: Das
authors.affiliation: Signal Transduction in Cancer and Stem Cells Laboratory, Department of Cancer Biology and Inflammatory Disorder, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), Kolkata, West Bengal, India.
authors.forename: Moumita
authors.initials: M
authors.lastname: Sarkar
authors.affiliation: Division of Pathology, Park Clinic, Kolkata, West Bengal, India.
authors.forename: Uttara
authors.initials: U
authors.lastname: Chatterjee
authors.affiliation: Division of Pathology, Park Clinic, Kolkata, West Bengal, India.
authors.forename: Sandip
authors.initials: S
authors.lastname: Chatterjee
authors.affiliation: Signal Transduction in Cancer and Stem Cells Laboratory, Department of Cancer Biology and Inflammatory Disorder, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), Kolkata, West Bengal, India.
authors.forename: Mrinal Kanti
authors.initials: MK
authors.lastname: Ghosh
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism*; D055354:Exosomes / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D051379:Mice; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D054730:Protein Interaction Domains and Motifs / Q000235:genetics; D059748:Proteolysis; D013379:Substrate Specificity; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D044767:Ubiquitin-Protein Ligases; D051059:PTEN Phosphohydrolase; D046988:Proteasome Endopeptidase Complex