title: Broad-spectrum anti-tumor and anti-metastatic DNA vaccine based on p62-encoding vector.
abstract: Autophagy plays an important role in neoplastic transformation of cells and in resistance of cancer cells to radio- and chemotherapy. p62 (SQSTM1) is a key component of autophagic machinery which is also involved in signal transduction. Although recent empirical observations demonstrated that p62 is overexpressed in variety of human tumors, a mechanism of p62 overexpression is not known. Here we report that the transformation of normal human mammary epithelial cells with diverse oncogenes (RAS, PIK3CA and Her2) causes marked accumulation of p62. Based on this result, we hypothesized that p62 may be a feasible candidate to be an anti-cancer DNA vaccine. Here we performed a preclinical study of a novel DNA vaccine encoding p62. Intramuscularly administered p62-encoding plasmid induced anti-p62 antibodies and exhibited strong antitumor activity in four models of allogeneic mouse tumors - B16 melanoma, Lewis lung carcinoma (LLC), S37 sarcoma, and Ca755 breast carcinoma. In mice challenged with Ca755 cells, p62 treatment had dual effect: inhibited tumor growth in some mice and prolonged life in those mice which developed tumor size similar to control. P62-encoding plasmid has demonstrated its potency both as a preventive and therapeutic vaccine. Importantly, p62 vaccination drastically suppressed metastasis formation: in B16 melanoma where tumor cells where injected intravenously, and in LLC and S37 sarcoma with spontaneous metastasis. Overall, we conclude that a p62-encoding vector(s) constitute(s) a novel, effective broad-spectrum antitumor and anti-metastatic vaccine feasible for further development and clinical trials.
authors.affiliation: Laboratory of Translational Biology, Department of Biology MCA, University of Camerino, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Venanzi
authors.forename: Victor
authors.initials: V
authors.lastname: Shifrin
authors.forename: Michael
authors.initials: M
authors.lastname: Sherman
authors.forename: Vladimir
authors.initials: V
authors.lastname: Gabai
authors.forename: Oleg
authors.initials: O
authors.lastname: Kiselev
authors.forename: Andrey
authors.initials: A
authors.lastname: Komissarov
authors.forename: Mikhail
authors.initials: M
authors.lastname: Grudinin
authors.forename: Maria
authors.initials: M
authors.lastname: Shartukova
authors.forename: Ekaterina A
authors.initials: EA
authors.lastname: Romanovskaya-Romanko
authors.forename: Yuri
authors.initials: Y
authors.lastname: Kudryavets
authors.forename: Natalya
authors.initials: N
authors.lastname: Bezdenezhnykh
authors.forename: Oleksandra
authors.initials: O
authors.lastname: Lykhova
authors.forename: Nadiia
authors.initials: N
authors.lastname: Semesyuk
authors.forename: Antonio
authors.initials: A
authors.lastname: Concetti
authors.forename: Anatoly
authors.initials: A
authors.lastname: Tsyb
authors.forename: Marina
authors.initials: M
authors.lastname: Filimonova
authors.forename: Victoria
authors.initials: V
authors.lastname: Makarchuk
authors.forename: Raisa
authors.initials: R
authors.lastname: Yakubovsky
authors.forename: Andrey
authors.initials: A
authors.lastname: Chursov
authors.forename: Vita
authors.initials: V
authors.lastname: Shcherbinina
authors.forename: Alexander
authors.initials: A
authors.lastname: Shneider
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D018827:Carcinoma, Lewis Lung / Q000276:immunology / Q000628:therapy; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005822:Genetic Vectors / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D006801:Humans; D008297:Male; D042361:Mammary Glands, Human / Q000378:metabolism / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000628:therapy; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D000071456:Sequestosome-1 Protein; D019444:Vaccines, DNA / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D019444:Vaccines, DNA