Inhibition of STAT3Y705 phosphorylation by Stattic suppresses proliferation and induces mitochondrial-dependent apoptosis in pancreatic cancer cells

Abstract

Patients with pancreatic cancer (PC) show dismal prognosis and high mortality. The development of PC is associated with the overactivation of STAT3. Here, we have determined that the non-peptide small molecule Stattic inhibits PC development by targeting STAT3. In vitro, Stattic treatment time- and dose-dependently inhibited proliferation of pancreatic cancer cells (PCCs) by reducing c-Myc expression and enhancing p53 activity. Consequently, p-Rb, cyclin D1, Chk1, and p21 (cell cycle proteins) were downregulated, and PCCs were arrested at the G1 phase, which was also confirmed by decreased Ki67 expression and unaltered PCNA expression. In addition, Stattic-induced mitochondrial-dependent apoptosis by elevating cleaved caspase-3, and Bax, cytochrome C levels, while reducing expression of Bcl-2, which may be regulated by reduced survivin expression. Further studies showed that Stattic exerts its anti-tumor effect via inhibition of STAT3Y705 phosphorylation and nuclear localization in PCCs. In a nude mouse tumorigenesis model, Stattic inhibited PC growth by antagonizing STAT3Y705 phosphorylation. Interleukin-6 used as a molecule agonist to activate STAT3, as well as overexpression of STAT3, could partially reverse Stattic-mediated anti-proliferation and pro-apoptotic effects of PCCs. Thus, these findings indicate that inhibition of STAT3Y705 phosphorylation by Stattic suppresses PCC proliferation and promotes mitochondrial-mediated apoptosis.

Sorafenib Chemosensitization by Caryophyllane Sesquiterpenes in Liver, Biliary, and Pancreatic Cancer Cells: The Role of STAT3/ABC Transporter Axis

“…However, it should be outlined that a different treatment protocol was used, thus partially explaining the difference observed. In any case, the literature reported controversial results in relation to the role of sorafenib in STAT3 regulation [30,64,65]; therefore, further mechanistic studies both in vitro and in vivo cancer models are expected.…”

“…The marked inhibition of STAT3 exerted by β-caryophyllene oxide could partly explain the higher sorafenib chemosensitization in Bx-PC3 cells with respect to β-caryophyllene. Indeed, several studies have shown that enhancing the STAT3 activation promotes pancreatic cancer malignance and is strongly associated with poor prognosis [30], thus suggesting that targeting STAT3 could potentially be exploited as a promising strategy to fight pancreatic cancer.…”

“…Taking into account the results obtained in the combination experiments that showed a potentiation of sorafenib cytotoxicity by caryophyllane sesquiterpenes, especially βcaryophyllene oxide, and the recognized involvement of ABC-transporters and STAT3 signaling in the progression and chemoresistance of hepato-biliary-pancreatic cancers [27][28][29][30][31][32][33], a possible modulation by treatments of this cascade in Bx-PC3, associated with the observed changes in MDR1 and MRPs pumps, was also evaluated (Figure 11). Activation of STAT3 by phosphorylation at tyrosine 705 (phospho(Tyr705)-STAT3), which is known to play an important role in the control of cell survival, proliferation, and apoptosis [34], has been measured.…”

IMB-0523 Inhibits Enterovirus 71 Replication by Activating Signal Transducer and Activator of Transcription 3 Signaling to Upregulate Interferon-Stimulated Genes Expression

“…Notably, the reduction of endogenous JAK1 or TYK2 by siRNA interference had no effect on the antiviral activity of IMB-0523 against EV71 [Figure 5B], but reducing the endogenous STAT3 by siRNA interference in HCT-8 cells attenuated the antiviral activity of IMB-0523 against EV71 [Figure 5B]. Moreover, stattic, a nonpeptide STAT3 small-molecule inhibitor that effectively inhibits STAT3 activation and nuclear translocation [22,23] also attenuated the antiviral activity of IMB-0523 against EV71 [Figure 5C]. Therefore, IMB-0523 can phosphorylate STAT3 by activating JAK1/TYK2 or directly activate STAT3 to initiate downstream signal transduction to inhibit EV71 replication [Figure 6].…”

Precision Nanomedicines: Targeting Hot Mitochondria in Cancer Cells

“…For example, inhibition of mitochondrial respiration could limit the energy supply given to cancer cells . Mitochondria-associated apoptosis , and autophagy can inhibit the growth of cancer cells. Furthermore, interfering and inhibiting mitochondrial metabolism can reduce the support for tumor anabolism, and increasing ROS levels in mitochondria can trigger the mitochondrial oxidative damage to induce the death of cancer cells …”