Disrupting VEGF-A paracrine and autocrine loops by targeting SHP-1 suppresses triple negative breast cancer metastasis

Abstract

Patients with triple-negative breast cancer (TNBC) had an increased likelihood of distant recurrence and death, as compared with those with non-TNBC subtype. Regorafenib is a multi-receptor tyrosine kinase (RTK) inhibitor targeting oncogenesis and has been approved for metastatic colorectal cancer and advanced gastrointestinal stromal tumor. Recent studies suggest regorafenib acts as a SHP-1 phosphatase agonist. Here, we investigated the potential of regorafenib to suppress metastasis of TNBC cells through targeting SHP-1/p-STAT3/VEGF-A axis. We found a significant correlation between cancer cell migration and SHP-1/p-STAT3/VEGF-A expression in human TNBC cells. Clinically, high VEGF-A expression is associated with worse disease-free and distant metastasis-free survival. Regorafenib induced significant anti-migratory effects, in association with downregulation of p-STAT3 and VEGF-A. To exclude the role of RTK inhibition in regorafenib-induced anti-metastasis, we synthesized a regorafenib derivative, SC-78, that had minimal effect on VEGFR2 and PDGFR kinase inhibition, while having more potent effects on SHP-1 activation. SC-78 demonstrated superior in vitro and in vivo anti-migration to regorafenib. Furthermore, VEGF-A dependent autocrine/paracrine loops were disrupted by regorafenib and SC-78. This study implies that SHP-1/p-STAT3/VEGF-A axis is a potential therapeutic target for metastatic TNBC, and the more potent SC-78 may be a promising lead for suppressing metastasis of TNBC.

Regorafenib inhibits tumor progression through suppression of ERK/NF-κB activation in hepatocellular carcinoma bearing mice

“…Regorafenib, a multikinase inhibitor, is used to treat different kinds of cancer. Su et al [ 19 ] found regorafenib reduced protein expression of VEGF through suppression of signal transducer and activator of transcription 3 (STAT-3) activation in triple negative breast cancer cells in vitro and in vivo . Chen et al [ 20 ] found regorafenib triggered p53-upregulated modulator of apoptosis (PUMA)-mediated apoptosis through induction of NF-κB pathway in colorectal cancer in vitro and in vivo .…”

WMJ‐8‐B, a novel hydroxamate derivative, induces MDA‐MB‐231 breast cancer cell death via the SHP‐1‐STAT3‐survivin cascade

“…The precise mechanisms underlying WMJ‐8‐B′s activation of SHP‐1 or Sp1 signalling in MDA‐MB‐231 cells remains to be elucidated. Su et al () recently showed that SHP‐1 expression is inversely correlated with STAT3 phosphorylation in human TNBC cell lines and clinical breast cancer specimens. We noted, in the siRNA experiments, that WMJ‐8‐B slightly increased SHP‐1 levels in MDA‐MB‐231 cells in the absence of SHP‐1 siRNA.…”

Sorafenib analogue SC‐60 induces apoptosis through the SHP‐1/STAT3 pathway and enhances docetaxel cytotoxicity in triple‐negative breast cancer cells

“…Nintedanib has been found to elevate SHP‐1 activity through interacting with SHP‐1 at Glu524 through hydrogen bonding in a docking model (Tai et al ., ). Although many SHP‐1 activators have been identified (Chen et al ., ,b,c; Liu et al ., ; Su et al ., ,b, ; Tai et al ., ), the structure and activity relationship still needs to be further investigated.…”