Luteolin selectively kills STAT3 highly activated gastric cancer cells through enhancing the binding of STAT3 to SHP-1

Abstract

The antitumor effect of luteolin, a plant flavonoid, in gastric cancer (GC) cells has not been fully understood. Here we show that luteolin selectively kills STAT3 overactivated GC cells that are often drug resistant. The treatment of luteolin in these GC cells significantly inhibited STAT3 phosphorylation and reduced the expression of STAT3 targeting gene Mcl-1, Survivin and Bcl-xl. Silencing of SHP-1, a protein tyrosine phosphatase, abolished the inhibitory effect of luteolin on STAT3 and cell apoptosis, suggesting that SHP-1 is crucial in luteolin-mediated cellular function. Moreover, this luteolin effect of STAT3 dephosphorylation by SHP-1 involved in HSP-90, which protected STAT3 phosphorylation by forming HSP-90/STAT3 complex. Thus, luteolin inhibited STAT3 activation through disrupting the binding of HSP-90 to STAT3, which promoted its interaction to SHP-1, resulted in the dephosphorylation of STAT3. The GC cell xenograft mouse model confirmed the effectiveness of luteolin induced inhibition of tumor growth in vivo.

HIF‐1α/VEGF signaling‐mediated epithelial–mesenchymal transition and angiogenesis is critically involved in anti‐metastasis effect of luteolin in melanoma cells

“…Luteolin (3′, 4′, 5, 7‐terahydroxyflavone) is a common effective dietary flavonoid that is present in fruits, vegetables, and medicinal herbs (Liu, Xu, Yan, Cheng, & Liu, ; Song et al, ). Furthermore, accumulating evidences have suggested that luteolin possesses multiple pharmacological activities such as anti‐inflammation, anti‐hypertension, antioxidant, and antitumor, which are also supposed to be the basis of these biological properties (Aziz, Kim, & Cho, ; Cui et al, ).…”

Allicin Inhibits Proliferation and Invasion in Vitro and in Vivo via SHP-1-Mediated STAT3 Signaling in Cholangiocarcinoma

“…Src homology region 2 (SH2) domain-containing phosphatase 1 (SHP-1) belongs to a family of non-receptor PTPs and has been identified as a negative regulator of numerous cytokine signaling pathways [19]. Previous studies have shown that SHP-1 tyrosine phosphatase, which negatively targets phosphorylated (p)-STAT3 signaling in a wide variety of tumors, exhibits significant anti-tumor activity by triggering apoptosis and suppressing tumor formation [20][21][22]. Consequently, the STAT3 pathway may represent a target for therapeutic intervention in CCA.…”

RING finger protein 38 induces gastric cancer cell growth by decreasing the stability of the protein tyrosine phosphatase SHP‐1

“…Previous study also showed that SHP-1 could be ubiquitinated for degradation, and RNF6 was an E3 ligase for SHP-1 ubiquitination in colorectal cancer [8]. In gastric cancer, SHP-1/STAT3 axis is important for gastric cancer tumorigenesis and can be as a target for drug discovery [17,31]. In gastric cancer, SHP-1/STAT3 axis is important for gastric cancer tumorigenesis and can be as a target for drug discovery [17,31].…”