Excessive activation of signal transducer and activator of transcription 3 (STAT3) signaling is observed in a subset of many cancers, making activated STAT3 a highly promising potential therapeutic target supported by multiple preclinical and clinical studies. However, early-phase clinical trials have produced mixed results with STAT3-targeted cancer therapies, revealing substantial complexity to targeting aberrant STAT3 signaling. This review discusses the diverse mechanisms of oncogenic activation of STAT3, and the small molecule inhibitors of STAT3 in cancer treatment.

The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) signaling system regulates a variety of biological processes, including embryogenesis, angiogenesis, wound repair, tissue homeostasis, and cancer. It exerts these regulatory functions by controlling proliferation, differentiation, migration, survival, and metabolism of target cells. The morphological structure of the lung is a complex tree-like network for effective oxygen exchange, and the airway terminates in the middle and distal ends of many alveoli. FGF/FGFR signaling plays an important role in the pathophysiology of lung development and pathogenesis of various human respiratory diseases. Here, we mainly review recent advances in FGF/FGFR signaling during human lung development and respiratory diseases, including lung cancer, acute lung injury (ALI), pulmonary arterial hypertension (PAH), chronic obstructive pulmonary disease (COPD), asthma, and pulmonary fibrosis.

Pulmonary arterial hypertension (PAH) is characterized by pulmonary arterial remodeling mainly due to excess cellular proliferation and apoptosis resistance of pulmonary arterial smooth muscle cells (PASMCs). Salidroside, an active ingredient isolated from Rhodiola rosea is proposed to exert protective effects against PAH. However, the function of salidroside in PAH has not been investigated systematically and the underlying mechanisms are not clear. To investigate the effects of salidroside on PAH, the mice in chronic hypoxia model of PAH were given by an increasing concentration of salidroside (0, 16 mg/kg, 32 mg/kg, and 64 mg/kg). After salidroside treatment, the chronic hypoxia-induced right ventricular hypertrophy and pulmonary arterial remodeling were attenuated, suggesting a protective role played by salidroside in PAH. To explore the potential mechanisms, the apoptosis of PASMCs after salidroside treatment under hypoxia conditions were determined in vivo and in vitro, and also the mitochondria-dependent apoptosis factors, Bax, Bcl-2, cytochrome C, and caspase 9 were examined. The results revealed that salidroside reversed hypoxia-induced cell apoptosis resistance at least partially via a mitochondria-dependent pathway. In addition, salidroside upregulated the expression of adenosine A2a receptor (A2aR) in lung tissues of mice and in PASMCs in vitro after hypoxia exposure. Combined the evidence above, we conclude that salidroside can attenuate chronic hypoxia-induced PAH by promoting PASMCs apoptosis via an A2aR related mitochondria dependent pathway.

Recent studies have shown that both adenosine monophosphate activated protein kinase (AMPK) and the mammalian target of rapamycin (mTOR) are energy sensors and are related to autophagy. Our recent reports have shown that salidroside can exert protective effects against hypoxia-induced pulmonary arterial smooth muscle cell (PASMC) proliferation and apoptosis resistance through the AMPK pathway. This study aims to explore the relationship among AMPK, mTOR and ULK1 in PASMCs under hypoxic conditions and to investigate whether the protective effects of salidroside are related to the autophagic cell death pathway. Rat PASMCs were cultured and divided into five groups: the normoxia, hypoxia, hypoxia + MHY1485 (mTOR agonist), hypoxia + rapamycin (mTOR inhibitor) and hypoxia + salidroside groups. Hypoxic cells were treated as indicated for 24 h. Cell viability was evaluated by the CCK-8 assay. Cell apoptosis was measured by the TUNEL assay. The autophagy flux of PASMCs was evaluated with tandem mRFP-GFP fluorescence microscopy. Autophagosomes were detected by electron microscopy. Protein expression of LC3, p62, AMPK, P-AMPK (Thr 172), P-ULK1 (Ser 555 and Ser 317), mTOR, P-mTOR (Ser 2448), ULK1 and P-ULK1 (Ser 757) was detected by western blot assay. PASMC proliferation and apoptosis resistance were observed under hypoxic conditions. Autophagy flux, the number of autophagosomes and the LC3II/LC3I ratio were increased in the hypoxia group compared with the normoxia group, whereas p62 expression was decreased. Treatment with rapamycin or salidroside reversed hypoxia-induced PASMC proliferation and apoptosis resistance and further increased autophagy flux, autophagosome levels and the LC3II/LC3I ratio but decreased p62 expression. Treatment with MHY1485 reversed hypoxia-induced PASMC apoptosis resistance and decreased autophagy flux as well as increased autophagosome levels, the LC3II/LC3I ratio and p62 expression. P-AMPK (Thr 172) and P-ULK1 (Ser 555) of the AMPK-ULK1 pathway were increased in the hypoxia group and were further increased in the salidroside group. Rapamycin and MHY1485 had no effect on either P-AMPK (Thr 172) or P-ULK1 (Ser 555). Phosphorylation of ULK1 at serine 317 did not significantly affect the five groups. Furthermore, P-mTOR (Ser 2448) and P-ULK1 (Ser 757) of the AMPK-mTOR-ULK1 pathway were decreased in the hypoxia group and were further decreased in the salidroside group. MHY1485 increased the expression of both P-mTOR(Ser 2448) and P-ULK1(Ser 757), whereas rapamycin had the opposite effect. Salidroside might inhibit hypoxia-induced PASMC proliferation and reverse apoptosis resistance via the upregulation of autophagy through both the AMPKα1-ULK1 and AMPKα1-mTOR-ULK1 pathways.

Rhein is a lipophilic anthraquinone extensively found in medicinal herbs. Emerging evidence suggests that rhein has significant antitumor effects, supporting its potential use as an antitumor agent. The IL6/STAT3 signaling pathway has been suggested as an attractive target for the discovery of novel cancer therapeutics. The human pancreatic cancer cell lines AsPC-1, Patu8988T, BxPC-3 and PANC-1, and immunodeficient mice were chosen as models to study the effects of rhein. The potent antiproliferative and proapoptotic effects of rhein were examined by cell viability, cellular morphology, apoptosis and colony formation assays. The STAT3 luciferase report assay, immunostaining analysis and Western blot analysis revealed the inhibition of the IL6/STAT3 signaling axis. Apoptosis was induced by adjunctive use of rhein with epidermal growth factor receptor (EGFR) inhibitors in pancreatic cancer cells as verified by cell apoptosis analysis and changes in the expression level of apoptotic/anti-apoptotic proteins BCL-2, BAX, Caspase 3 and Cl-PARP. Suppression of the phosphorylation of STAT3 and EGFR were also observed as a result of the treatment with a combination of rhein and EGFR inhibitors. Most interestingly, it was found that rhein considerably sensitized cells to erlotinib, thus suppressing tumor growth in PANC-1 and BxPC-3 xenograft models. The in vivo anti-tumor effect was associated with increased apoptosis and combined inhibition of the STAT3 and EGFR pathways in tumor remnants. Rhein sensitizes human pancreatic cancer cells to EGFR inhibitors through inhibition of STAT3. Taken together, the results indicate that rhein offers a novel blueprint for pancreatic cancer therapy, particularly when combined with EGFR inhibitors.