Open AccessSorafenib analogue SC ‐60 induces apoptosis through the SHP ‐1/ STAT 3 pathway and enhances docetaxel cytotoxicity in triple‐negative breast cancer cells
Author(s) -
Liu ChunYu,
Su JungChen,
Huang TzuTing,
Chu PeiYi,
Huang ChunTeng,
Wang WanLun,
Lee ChiaHan,
Lau KaYi,
Tsai WenChun,
Yang HsiuPing,
Shiau ChungWai,
Tseng LingMing,
Chen KuenFeng
Publication year - 2017
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.12033
Subject(s) - triple negative breast cancer , cancer research , docetaxel , apoptosis , proto oncogene tyrosine protein kinase src , sorafenib , chemistry , signal transduction , biology , medicine , cancer , breast cancer , biochemistry , hepatocellular carcinoma
Recurrent triple‐negative breast cancer ( TNBC ) needs new therapeutic targets. Src homology region 2 domain‐containing phosphatase‐1 ( SHP ‐1) can act as a tumor suppressor by dephosphorylating oncogenic kinases. One major target of SHP ‐1 is STAT 3, which is highly activated in TNBC . In this study, we tested a sorafenib analogue SC ‐60, which lacks angiokinase inhibition activity, but acts as a SHP ‐1 agonist, in TNBC cells. SC ‐60 inhibited proliferation and induced apoptosis by dephosphorylating STAT 3 in both a dose‐ and time‐dependent manner in TNBC cells ( MDA ‐ MB ‐231, MDA ‐ MB ‐468, and HCC 1937). By contrast, ectopic expression of STAT 3 rescued the anticancer effect induced by SC ‐60. SC ‐60 also increased the SHP ‐1 activity, but this effect was inhibited when the N‐ SH 2 domain ( DN 1) was deleted or with SHP ‐1 point mutation (D61A), implying that SHP ‐1 is the major target of SC ‐60 in TNBC . The use of SC ‐60 in combination with docetaxel synergized the anticancer effect induced by SC ‐60 through the SHP ‐1/ STAT 3 pathway in TNBC cells. Importantly, SC ‐60 also displayed a significant antitumor effect in an MDA ‐ MB ‐468 xenograft model by modulating the SHP ‐1/ STAT 3 axis, indicating the anticancer potential of SC ‐60 in TNBC treatment. Targeting SHP ‐1/p‐ STAT 3 and the potential combination of SHP ‐1 agonist with chemotherapeutic docetaxel is a feasible therapeutic strategy for TNBC .