PMID- 32054892
OWN - NLM
STAT- MEDLINE
DCOM- 20201116
LR  - 20210212
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 10
IP  - 1
DP  - 2020 Feb 13
TI  - The anti-tumoral potential of the saporin-based uPAR-targeting chimera ATF-SAP.
PG  - 2521
LID - 10.1038/s41598-020-59313-8 [doi]
LID - 2521
AB  - The development of personalized therapies represents an urgent need owing to the 
      high rate of cancer recurrence and systemic toxicity of conventional drugs. So 
      far, targeted toxins have shown promising results as potential therapeutic 
      compounds. Specifically, toxins conjugated to antibodies or fused to growth 
      factors/enzymes have been largely demonstrated to selectively address and kill 
      cancer cells. We investigated the anti-tumor potential of a chimeric recombinant 
      fusion protein formed by the Ribosome Inactivating Protein saporin (SAP) and the 
      amino-terminal fragment (ATF) of the urokinase-type plasminogen activator (uPA), 
      whose receptor has been shown to be over-expressed on the surface of aggressive 
      tumors. ATF-SAP was recombinantly produced by the P. pastoris yeast and its 
      activity was assessed on a panel of bladder and breast cancer cell lines. ATF-SAP 
      resulted to be highly active in vitro, as nano-molar concentrations were 
      sufficient to impair viability on tumor cell lines. In contrast to untargeted 
      toxins, the chimeric fusion protein displayed a significantly improved toxic 
      effect in uPAR-expressing cells, demonstrating that the selective activity was 
      due to the presence of the targeting moiety. Fibroblasts were not sensitive to 
      ATF-SAP despite uPAR expression, indicating that cell-specific receptor-mediated 
      internalization pathway(s) might be considered. The in vivo anti-tumor effect of 
      the chimera was shown in a bladder cancer xenograft model. Current findings 
      indicate ATF-SAP as a suitable anti-tumoral therapeutic option to cope with 
      cancer aggressiveness, as a single treatment or in combination with traditional 
      therapeutic approaches, to appropriately address the intra- and inter- tumor 
      heterogeneity.
FAU - Zuppone, S
AU  - Zuppone S
AD  - Urological Research Institute, Division of Experimental Oncology, IRCCS San 
      Raffaele Scientific Institute, Milano, Italy.
FAU - Assalini, C
AU  - Assalini C
AD  - Urological Research Institute, Division of Experimental Oncology, IRCCS San 
      Raffaele Scientific Institute, Milano, Italy.
FAU - Minici, C
AU  - Minici C
AUID- ORCID: 0000-0002-8350-484X
AD  - Biocrystallography Unit, Division of Immunology, Transplantation, and Infectious 
      Diseases, IRCCS San Raffaele Scientific Institute, Milano, Italy.
FAU - Bertagnoli, S
AU  - Bertagnoli S
AD  - Dipartimento di Biotecnologie e Bioscienze, Universita degli Studi di 
      Milano-Bicocca, Milan, Italy.
FAU - Branduardi, P
AU  - Branduardi P
AD  - Dipartimento di Biotecnologie e Bioscienze, Universita degli Studi di 
      Milano-Bicocca, Milan, Italy.
FAU - Degano, M
AU  - Degano M
AUID- ORCID: 0000-0002-0787-1883
AD  - Biocrystallography Unit, Division of Immunology, Transplantation, and Infectious 
      Diseases, IRCCS San Raffaele Scientific Institute, Milano, Italy.
FAU - Fabbrini, M S
AU  - Fabbrini MS
AD  - MIUR, Italian Ministry of Instruction, University and Research, 20090, Monza, 
      Italy.
FAU - Montorsi, F
AU  - Montorsi F
AD  - Urological Research Institute, Division of Experimental Oncology, IRCCS San 
      Raffaele Scientific Institute, Milano, Italy.
AD  - Universita Vita-Salute San Raffaele, Milano, Italy.
FAU - Salonia, A
AU  - Salonia A
AD  - Urological Research Institute, Division of Experimental Oncology, IRCCS San 
      Raffaele Scientific Institute, Milano, Italy.
AD  - Universita Vita-Salute San Raffaele, Milano, Italy.
FAU - Vago, R
AU  - Vago R
AD  - Urological Research Institute, Division of Experimental Oncology, IRCCS San 
      Raffaele Scientific Institute, Milano, Italy. vago.riccardo@hsr.it.
AD  - Universita Vita-Salute San Raffaele, Milano, Italy. vago.riccardo@hsr.it.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200213
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Receptors, Urokinase Plasminogen Activator)
RN  - 0 (Recombinant Fusion Proteins)
RN  - EC 3.2.2.22 (Saporins)
RN  - EC 3.4.21.73 (Urokinase-Type Plasminogen Activator)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/*pharmacology
MH  - Cell Line, Tumor
MH  - Cell Survival/drug effects
MH  - Female
MH  - Humans
MH  - Mice
MH  - Mice, Nude
MH  - Neoplasms/*drug therapy/pathology
MH  - Receptors, Urokinase Plasminogen Activator/analysis
MH  - Recombinant Fusion Proteins/pharmacology
MH  - Saporins/*pharmacology
MH  - Triple Negative Breast Neoplasms/drug therapy/pathology
MH  - Urinary Bladder Neoplasms/drug therapy/pathology
MH  - Urokinase-Type Plasminogen Activator/*pharmacology
PMC - PMC7018701
COIS- The authors declare no competing interests.
EDAT- 2020/02/15 06:00
MHDA- 2020/11/18 06:00
PMCR- 2020/02/13
CRDT- 2020/02/15 06:00
PHST- 2019/08/06 00:00 [received]
PHST- 2020/01/23 00:00 [accepted]
PHST- 2020/02/15 06:00 [entrez]
PHST- 2020/02/15 06:00 [pubmed]
PHST- 2020/11/18 06:00 [medline]
PHST- 2020/02/13 00:00 [pmc-release]
AID - 10.1038/s41598-020-59313-8 [pii]
AID - 59313 [pii]
AID - 10.1038/s41598-020-59313-8 [doi]
PST - epublish
SO  - Sci Rep. 2020 Feb 13;10(1):2521. doi: 10.1038/s41598-020-59313-8.