PMID- 33167431
OWN - NLM
STAT- MEDLINE
DCOM- 20210421
LR  - 20210421
IS  - 1420-3049 (Electronic)
IS  - 1420-3049 (Linking)
VI  - 25
IP  - 21
DP  - 2020 Nov 5
TI  - Targeting TGF-beta-Mediated SMAD Signaling Pathway via Novel Recombinant Cytotoxin 
      II: A Potent Protein from Naja naja oxiana Venom in Melanoma.
LID - 10.3390/molecules25215148 [doi]
LID - 5148
AB  - Since the current treatments have not resulted in the desired outcomes for 
      melanoma patients, there is a need to identify more effective medications. 
      Together with other snake venom proteins, cytotoxin-II has shown promising 
      results in tumoral cells. In this study, recombinant cytotoxin-II (rCTII) was 
      expressed in SHuffle((R)) T7 Express cells, while the epitope mapping of rCTII was 
      performed to reveal the antibody-binding regions of rCTII. The MTT 
      (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay was used to 
      assess the viability of SK-MEL-3 and HFF-2 cells after treating these cells with 
      rCTII. The qRT-PCR was performed to evaluate the expression levels of matrix 
      metallopeptidase 3 (MMP-3), SMAD2, SMAD3, caspase-8, caspase-9, and miR-214 in 
      order to reveal the rCTII-induced signaling pathways in melanoma. Our results 
      have shown that two regions of amino acids, 6-16 and 19-44, as predicted epitopes 
      of this toxin, are essential for understanding the toxicity of rCTII. Treating 
      the melanoma cells with rCTII substantially inhibited the transforming growth 
      factor-beta (TGF-beta)-SMAD signaling pathway and down-regulated the expression of 
      MMP-3 and miR-214 as well. This cytotoxin also restored apoptosis mainly via the 
      intrinsic pathway. The down-regulation of MMP-3 and miR-214 might be associated 
      with the anti-metastatic property of rCTII in melanoma. The inhibitory effect of 
      rCTII on the TGF-beta signaling pathway might be associated with increased apoptosis 
      and decreased cancer cell proliferation. It is interesting to see that the IC50 
      value of rCTII has been lower in the melanoma cells than non-tumoral cells, which 
      may indicate its potential effects as a drug. In conclusion, rCTII, as a novel 
      medication, might serve as a potent and efficient anticancer drug in melanoma.
FAU - Derakhshani, Afshin
AU  - Derakhshani A
AUID- ORCID: 0000-0002-3243-233X
AD  - Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 
      51656-65811, Iran.
AD  - IRCCS Istituto Tumori "Giovanni Paolo II" of Bari, 70124 Bari, Italy.
FAU - Silvestris, Nicola
AU  - Silvestris N
AUID- ORCID: 0000-0001-7814-7318
AD  - IRCCS Istituto Tumori "Giovanni Paolo II" of Bari, 70124 Bari, Italy.
AD  - Department of Biomedical Sciences and Human Oncology (DIMO), University of Bari, 
      70124 Bari, Italy.
FAU - Hemmat, Nima
AU  - Hemmat N
AUID- ORCID: 0000-0001-6432-9647
AD  - Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 
      51656-65811, Iran.
FAU - Asadzadeh, Zahra
AU  - Asadzadeh Z
AD  - Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 
      51656-65811, Iran.
FAU - Abdoli Shadbad, Mahdi
AU  - Abdoli Shadbad M
AUID- ORCID: 0000-0003-4865-8779
AD  - Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 
      51656-65811, Iran.
FAU - Nourbakhsh, Niloufar Sadat
AU  - Nourbakhsh NS
AD  - Department of Biology, Islamic Azad University, Varamin-Pishva Branch, Varamin, 
      Tehran 33817-74895, Iran.
FAU - Mobasheri, Leila
AU  - Mobasheri L
AUID- ORCID: 0000-0003-3470-0278
AD  - Department of Immunology, Faculty of Medicine, Birjand University of Medical 
      Sciences, Birjand 97178-53577, Iran.
FAU - Vahedi, Parviz
AU  - Vahedi P
AD  - Department of Anatomical Sciences, Maragheh University of Medical Sciences, 
      Maragheh 51656-65931, Iran.
FAU - Shahmirzaie, Morteza
AU  - Shahmirzaie M
AD  - Pharmaceutical Sciences Research Center, Shahid Beheshti University of Medical 
      Sciences, Niayesh Highway, Valiasr Ave, Tehran 19919-53381, Iran.
FAU - Brunetti, Oronzo
AU  - Brunetti O
AUID- ORCID: 0000-0002-7014-6828
AD  - IRCCS Istituto Tumori "Giovanni Paolo II" of Bari, 70124 Bari, Italy.
FAU - Safarpour, Hossein
AU  - Safarpour H
AUID- ORCID: 0000-0001-9883-9186
AD  - Cellular & Molecular Research Center, Birjand University of Medical Sciences, 
      Birjand 97178-53577, Iran.
FAU - Baradaran, Behzad
AU  - Baradaran B
AUID- ORCID: 0000-0002-8642-6795
AD  - Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 
      51656-65811, Iran.
AD  - Department of Immunology, Faculty of Medicine, Tabriz University of Medical 
      Sciences, Tabriz 51666-14766, Iran.
LA  - eng
PT  - Journal Article
DEP - 20201105
PL  - Switzerland
TA  - Molecules
JT  - Molecules (Basel, Switzerland)
JID - 100964009
RN  - 0 (Cytotoxins)
RN  - 0 (Epitopes)
RN  - 0 (Immunoglobulin G)
RN  - 0 (MIRN214 microRNA, human)
RN  - 0 (MicroRNAs)
RN  - 0 (Recombinant Proteins)
RN  - 0 (SMAD2 protein, human)
RN  - 0 (SMAD3 protein, human)
RN  - 0 (Smad2 Protein)
RN  - 0 (Smad3 Protein)
RN  - 0 (Snake Venoms)
RN  - 0 (TGFB1 protein, human)
RN  - 0 (Transforming Growth Factor beta1)
SB  - IM
MH  - Animals
MH  - Apoptosis
MH  - Cell Proliferation
MH  - Cell Survival
MH  - Cytotoxins/*chemistry
MH  - Epitope Mapping
MH  - Epitopes/chemistry
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - Humans
MH  - Immunoglobulin G/chemistry
MH  - Inhibitory Concentration 50
MH  - Melanoma/*drug therapy
MH  - MicroRNAs/metabolism
MH  - Naja naja
MH  - Neoplasm Metastasis
MH  - Recombinant Proteins/chemistry
MH  - Signal Transduction
MH  - Skin Neoplasms/*drug therapy
MH  - Smad2 Protein/*metabolism
MH  - Smad3 Protein/metabolism
MH  - Snake Venoms/*chemistry
MH  - Transforming Growth Factor beta1/*metabolism
PMC - PMC7663949
OTO - NOTNLM
OT  - TGF-beta pathway
OT  - apoptosis
OT  - melanoma
OT  - recombinant cytotoxin-II
OT  - snake venom
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2020/11/11 06:00
MHDA- 2021/04/22 06:00
PMCR- 2020/11/05
CRDT- 2020/11/10 01:05
PHST- 2020/10/15 00:00 [received]
PHST- 2020/10/29 00:00 [revised]
PHST- 2020/11/02 00:00 [accepted]
PHST- 2020/11/10 01:05 [entrez]
PHST- 2020/11/11 06:00 [pubmed]
PHST- 2021/04/22 06:00 [medline]
PHST- 2020/11/05 00:00 [pmc-release]
AID - molecules25215148 [pii]
AID - molecules-25-05148 [pii]
AID - 10.3390/molecules25215148 [doi]
PST - epublish
SO  - Molecules. 2020 Nov 5;25(21):5148. doi: 10.3390/molecules25215148.