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There is increasing global incidence of highly metastatic melanoma and therapeutic strategies like those focusing on the downstream beta-catenin/MITF axis of invading melanoma cells are urgently needed. Targeting endoplasmic reticulum (ER) stress can promote cancer cell death and inhibit epithelial mesenchymal transition (EMT) in metastatic tumors. This study aimed to determine if Honokiol could promote ER stress-dependent apoptosis and regulate metastatic melanoma. The therapeutic efficacy of Honokiol was assessed using the highly metastatic melanoma xenograft mouse model for peritoneal metastasis and evaluated by computed tomography imaging. The ER stress marker, Calpain-10, delineated a novel proteolytic cleavage enzyme, while CHOP/GADD153-regulated apoptosis was used for gene silencing to determine the role of the β-catenin/MITF axis in melanoma cells. The results showed that Honokiol effectively decreased peritoneal dissemination and organ metastasis via ER stress activation and EMT marker inhibition. Knockdown Calpain-10 or CHOP/GADD153 blocked all of the biological effects in Honokiol-induced β-catenin/MITF cleavage, ERSE or TCF/LEF luciferase activity, and β-catenin kinase activity. These findings suggest that Honokiol can significantly thwart the progression of highly metastatic melanoma using the β-catenin/MITF axis via prompt Calpain-10 and CHOP/GADD153 regulated cascades. [ABSTRACT FROM AUTHOR]

Activating germline mutations of anaplastic lymphoma kinase (ALK) occur in most cases of hereditary neuroblastoma (NB) and the constitutively active kinase activity of ALK promotes cell proliferation and survival in NB. Therefore, ALK kinase is a potential therapeutic target for NB. In this study, we show that the novel ALK inhibitor alectinib effectively suppressed cell proliferation and induces apoptosis in NB cell lines with either wild-type ALK or mutated ALK (F1174L and D1091N) by blocking ALK-mediated PI3K/Akt/mTOR signaling. In addition, alectinib enhanced doxorubicin-induced cytotoxicity and apoptosis in NB cells. Furthermore, alectinib induced apoptosis in an orthotopic xenograft NB mouse model. Also, in the TH-MYCN transgenic mouse model, alectinib resulted in decreased tumor growth and prolonged survival time. These results indicate that alectinib may be a promising therapeutic agent for the treatment of NB. [ABSTRACT FROM AUTHOR]

Transforming growth factor-β1 (TGF-β1) promotes tumor metastasis by inducing an epithelial-to-mesenchymal transition (EMT) in cancer cells. In this study, we investigated the effects of BIX02189 and XMD8-92, pharmacologic inhibitors of the MEK5 [mitogen-activated protein kinase/extracellular-signal-regulated kinase (ERK)5] signaling pathway, on the EMT and migration of cancer cells induced by TGF-β1. In human A549 lung cancer cells, TGF-β1-induced EMT, cell motility, and expression of matrix metalloproteinase-2 were completely inhibited by BIX02189, but not by XMD8-92 or small interference RNAs specific to MEK5 and ERK5. Interestingly, BIX02189 strongly blocked the activation of TGF-β1 signaling components, and this inhibitory effect was not reproduced by MEK5 inhibition. Molecular docking simulation and kinase assays revealed that BIX02189 binds directly to the ATP-binding site of the TGF-β receptor type I (TβRI) and suppresses its kinase activity. Finally, the anti-metastatic effect of BIX02189 was validated in a TβRI-derived A549 xenograft mouse model. Collectively, these findings newly characterize BIX02189 as a potent inhibitor of TβRI that can block the tumor metastatic activity of TGF-β1. [ABSTRACT FROM AUTHOR]

Dysregulation in iron metabolism can lead to a wide range of diseases including cancer. Iron-regulatory proteins (IRPs) and iron responsive elements (IREs) have been established as post-transcriptional regulators of intracellular iron homeostasis. The roles of other pathways involved in this process, however, remain largely unknown. Here we report that epidermal growth factor receptor (EGFR), an oncogenic driver, binds to and regulates the subcellular distribution of transferrin receptor 1(TfR1) through its tyrosine kinase activity and thus is required for cellular iron import. Inactivation of EGFR reduces the cell surface TfR1 expression, which leads to decreased iron import due to impaired TfR1-mediated iron uptake. This damaged iron assimilation results in cell cycle arrest and growth inhibition, which can be partially rescued by non-Tf-bound iron supplements. Evaluation of non-small cell lung cancer samples reveals a positive correlation between EGFR activation and membrane TfR1 expression. Our findings uncover a new role of EGFR in modulating cellular iron homeostasis through redistribution of TfR1, which is essential for cancer development and progression. [ABSTRACT FROM AUTHOR]

Insulin-like growth factor I receptor (IGF1R) is frequently upregulated in breast cancer. Due to its intrinsic tyrosine kinase activity, aberrant activation of the IGF1R signaling axis may enhance tumor cell proliferation and cancer stemness, causing tumor relapse, metastasis and resistance to chemotherapy. We utilized a chromatin RNA in situ reverse transcription (CRIST) approach to characterize molecular factors that regulate the IGF1R network. We identified lncRNA HULC (Highly Upregulated in Liver Cancer) as a key trans-regulator of IGF1R in breast cancer cells. Loss of HULC suppressed the expression of IGF1R and the activation of its downstream PI3K/AKT pathway, while HULC overexpression activated the axis in breast cancer cells. Using a transcription-associated trap (RAT) assay, we demonstrated that HULC functioned as a nuclear lncRNA and epigenetically activated IGF1R by directly binding to the intragenic regulatory elements of the gene, orchestrating intrachromosomal interactions, and promoting histone H3K9 acetylation. The activated HULC-IGF1R/PI3K/AKT pathway mediated tumor resistance to cisplatin through the increased expression of cancer stemness markers, including NANOG, SOX2, OCT4, CD44 and ALDH1A1. In immunodeficient mice, stimulation of the HULC-IGF1R pathway promoted tumor metastasis. These data suggest that HULC may be a new epigenetic target for IGF1R axis-targeted therapeutic intervention. [ABSTRACT FROM AUTHOR]

Platelet-derived growth factor receptors (PDGFRα/β) play critical roles in the autocrine-stimulated growth and recruitment of cancer-associated fibroblasts (CAFs) of human lung cancer cells. We have identified GZD856 as a new PDGFR inhibitor that potently inhibits PDGFRα/β kinase activity and blocks this signaling pathway in lung cancer cells both in vitro and in vivo. GZD856 strongly suppresses the proliferation of PDGFRα-amplified H1703 (PDGFRβ(-)) human lung cancer cells and demonstrates significant in vivo antitumor efficacy in a xenograft mouse model. Although GZD856 displays only limited in vitro antiproliferative efficiency against PDGFRα(-)/PDGFRβ(+) A549 lung cancer cells, it efficiently inhibits the in vivo growth and metastasis of A549 cancer cells in xenograft and orthotopic models, respectively. The promising in vivo antitumor activity of GZD856 in A549 models may result from its suppression of PDGFR-related microenvironment factors, such as recruitment of CAFs and collagen content in stromal cells. GZD856 may be considered as a promising new candidate for anti-lung cancer drug development. [ABSTRACT FROM AUTHOR]

Mutant Kras and chronic pancreatitis are the most common pathological events involved in human pancreatic cancer. It has been demonstrated that c-Raf is responsible for transmitting signals from mutant Ras to its downstream signals including MEK-ERK and for initiating carcinogenesis. The soluble epoxide hydrolase (sEH), a pro-inflammatory enzyme, generally inactivates anti-inflammatory and anti-pain epoxyeicosatrienoic acids (EETs). Herein, we have synthesized a novel compound of trans-4-{4-[3-(4-chloro-3-trifluoromethyl-phenyl)-ureido]-cyclohexyloxy}-pyridine-2-carboxylic acid methylamide (t-CUPM) via modifying the central phenyl ring of sorafenib and confirmed its dual inhibition of sEH and c-Raf by recombinant kinase activity assay. Pharmacokinetic analysis revealed that oral dosing of t-CUPM resulted in higher blood levels than that of sorafenib throughout the complete time course (48 h). The effect of t-CUPM on the inhibition of mutant Kras(G12D)-initiated murine pancreatic cancer cell growth was determined using the mouse pancreatic carcinoma cell model obtained from LSL-Kras(G12D)/Pdx1-Cre mice and showed that t-CUPM significantly inhibited this murine pancreatic carcinoma cell growth both in vitro and in mice in vivo. Inhibition of mutant Kras-transmitted phosphorylations of cRAF/MEK/ERK was demonstrated in these pancreatic cancer cells using Western blot assay and immunohistochemical approach. Modulation of oxylipin profile, particularly increased EETs/DHET ratio by sEH inhibition, was observed in mice treated with t-CUPM. These results indicate that t-CUPM is a highly potential agent to treat pancreatic cancer via simultaneously targeting c-Raf and sEH. [ABSTRACT FROM AUTHOR]