The Transforming Growth Factor Beta 1/SMAD Signaling Pathway Involved in Human Chronic Myeloid Leukemia

Chronic Myeloid Leukemia (CML) is a rare malignant proliferative disease of the hematopoietic system, whose molecular hallmark is the Philadelphia chromosome (Ph). The Ph chromosome originates an aberrant fusion gene with abnormal kinase activity, leading to the buildup of reactive oxygen species and genetic instability of relevance in disease progression. Several genetic abnormalities have been correlated with CML in the blast phase, including chromosomal aberrations and common altered genes. Some of these genes are involved in the regulation of cell apoptosis and proliferation, such as the epidermal growth factor receptor (EGFR), tumor protein p53 (TP53), or Schmidt-Ruppin A-2 proto-oncogene (SRC); cell adhesion, e.g., catenin beta 1(CTNNB1); or genes associated to TGF-β, such as SKI like proto-oncogene (SKIL), transforming growth factor beta 1 (TGFB1) or transforming growth factor beta 2 (TGFB2); and TNF-α pathways, such as Tumor necrosis factor (TNFA) or Nuclear factor kappa B subunit 1 (NFKB1). The involvement of miRNAs in CML is also gaining momentum, where dysregulation of some critical miRNAs, such as miRNA-451 and miRNA-21, which have been associated to the molecular modulation of pathogenesis, progression of disease states, and response to therapeutics. In this review, the most relevant genomic alterations found in CML will be addressed.

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Parenchymal transforming growth factor beta-1: Its type II receptor and Smad signaling pathway correlate with inflammation and fibrosis in chronic liver disease of viral etiology

Journal of Gastroenterology and Hepatology ◽

10.1046/j.1440-1746.2003.03162.x ◽

2003 ◽

Vol 18 (11) ◽

pp. 1302-1308 ◽

Cited By ~ 27

Author(s):

FIORELLA CALABRESE ◽

MARIALUISA VALENTE ◽

CINZIA GIACOMETTI ◽

ELENA PETTENAZZO ◽

LUISA BENVEGNU ◽

...

Keyword(s):

Liver Disease ◽

Growth Factor ◽

Chronic Liver Disease ◽

Signaling Pathway ◽

Transforming Growth Factor Beta ◽

Transforming Growth Factor ◽

Type Ii ◽

Viral Etiology ◽

Smad Signaling Pathway ◽

Growth Factor Beta

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Targeting TGF-β-Mediated SMAD Signaling Pathway via Novel Recombinant Cytotoxin II: A Potent Protein from Naja naja oxiana Venom in Melanoma

Molecules ◽

10.3390/molecules25215148 ◽

2020 ◽

Vol 25 (21) ◽

pp. 5148

Author(s):

Afshin Derakhshani ◽

Nicola Silvestris ◽

Nima Hemmat ◽

Zahra Asadzadeh ◽

Mahdi Abdoli Shadbad ◽

...

Keyword(s):

Signaling Pathway ◽

Transforming Growth Factor Beta ◽

Transforming Growth Factor ◽

Inhibitory Effect ◽

Melanoma Cells ◽

Smad Signaling ◽

Diphenyltetrazolium Bromide ◽

Smad Signaling Pathway ◽

Matrix Metallopeptidase ◽

Tumoral Cells

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® 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-β)–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-β 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.

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