Inhibition of SHP2 by new compounds induces differential effects on RAS/RAF/ERK and PI3K/AKT pathways in different cancer cell types View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2018-06-27

AUTHORS

Cijo George Vazhappilly, Ekram Saleh, Wafaa Ramadan, Varsha Menon, Aya Mudhafar Al-Azawi, Hamadeh Tarazi, Hajjaj Abdu-Allah, Abdel-Nasser El-Shorbagi, Raafat El-Awady

ABSTRACT

Kinases and phosphatases are important players in growth signaling and are involved in cancer development. For development of targeted cancer therapy, attention is given to kinases rather than phosphatases inhibitors. Src homology region 2 domain-containing protein tyrosine phosphatase2 (SHP2) is overexpressed in different types of cancers. We investigated the SHP2-inhibitory effects of two new 5-aminosalicylate–4-thiazolinones in human cervical (HeLa) and breast (MCF-7 & MDA-MB-231) cancer cells. In-silico molecular docking showed preferential affinity of the two compounds towards the catalytic over the allosteric site of SHP2. An enzymatic assay confirmed the docking results whereby 0.01 μM of both compounds reduced SHP2 activity to 50%. On cellular level, the two compounds significantly reduced the expression of SHP2, KRAS, p-ERK and p-STAT3 in HeLa but not in the other two cell lines. Phosphorylation of AKT and JNK was enhanced in HeLa and MCF7. Both compounds exhibited anti-proliferative/anti-migratory effects on HeLa and MCF7 but not in MDA-MB-231 cells. These results indicate that inhibition of SHP2 and its downstream pathways by the two compounds might be a promising strategy for cancer therapy in some but not all cancer types. More... »

PAGES

252-261

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s10637-018-0626-5

DOI

http://dx.doi.org/10.1007/s10637-018-0626-5

DIMENSIONS

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PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/29947013


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79 domain-containing protein tyrosine phosphatase2
80 downstream pathways
81 effect
82 enzymatic assay
83 expression
84 expression of SHP2
85 growth
86 homology region 2 domain-containing protein tyrosine phosphatase2
87 important players
88 inhibition
89 inhibition of SHP2
90 inhibitors
91 kinase
92 levels
93 lines
94 molecular docking
95 new compounds
96 pathway
97 phosphatase
98 phosphatase2
99 phosphorylation
100 phosphorylation of Akt
101 players
102 preferential affinity
103 promising strategy
104 protein tyrosine phosphatase2
105 region 2 domain-containing protein tyrosine phosphatase2
106 results
107 silico molecular docking
108 sites
109 strategies
110 therapy
111 types
112 tyrosine phosphatase2
113 μM
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