Targeting LRRC15 Inhibits Metastatic Dissemination of Ovarian Cancer.

Dissemination of ovarian cancer cells can lead to inoperable metastatic lesions in the bowel and omentum that cause patient death. Here we show that LRRC15, a type-I 15-leucine-rich repeat-containing membrane protein, highly overexpressed in ovarian cancer bowel metastases compared with matched primary tumors and acts as a potent promoter of omental metastasis. Complementary models of ovarian cancer demonstrated that LRRC15 expression leads to inhibition of anoikis-induced cell death and promotes adhesion and invasion through matrices that mimic omentum.

Quinacrine Induces Nucleolar Stress in Treatment-Refractory Ovarian Cancer Cell Lines.

A considerable subset of gynecologic cancer patients experience disease recurrence or acquired resistance, which contributes to high mortality rates in ovarian cancer (OC). Our prior studies showed that quinacrine (QC), an antimalarial drug, enhanced chemotherapy sensitivity in treatment-refractory OC cells, including artificially generated chemoresistant and high-grade serous OC cells. In this study, we investigated QC-induced transcriptomic changes to uncover its cytotoxic mechanisms of action.

Corrigendum to "Activation of AMP-Activated Protein Kinase and Extracelluar Signal-Regulated Kinase Mediates CB-PIC-Induced Apoptosis in Hypoxic SW620 Colorectal Cancer Cells".

[This corrects the article DOI: 10.1155/2013/974313.].

Correction: The heparan sulfate mimetic PG545 interferes with Wnt/β-catenin signaling and significantly suppresses pancreatic tumorigenesis alone and in combination with gemcitabine.

[This corrects the article DOI: 10.18632/oncotarget.3214.

PFKFB3 inhibition reprograms malignant pleural mesothelioma to nutrient stress-induced macropinocytosis and ER stress as independent binary adaptive responses.

The metabolic signatures of cancer cells are often associated with elevated glycolysis. Pharmacological (PFK158 treatment) and genetic inhibition of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), a critical control point in the glycolytic pathway, decreases glucose uptake, ATP production, and lactate dehydrogenase activity and arrests malignant pleural mesothelioma (MPM) cells in the G0/G1 phase to induce cell death. To overcome this nutrient stress, inhibition of PFKFB3 activity led to an escalation in endoplasmic reticulum (ER) activity and aggravated ER stress mostly by upregulating BiP and GADD153 expression and activation of the endocytic Rac1-Rab5-Rab7 pathway resulting in a unique form of cell death called "methuosis" in both the sarcomatoid (H28) and epithelioid (EMMeso) cells.

Erratum to "Melatonin Suppresses the Expression of 45S Preribosomal RNA and Upstream Binding Factor and Enhances the Antitumor Activity of Puromycin in MDA-MB-231 Breast Cancer Cells".

[This corrects the article DOI: 10.1155/2013/879746.].

Genes associated with bowel metastases in ovarian cancer.

Objective: This study is designed to identify genes and pathways that could promote metastasis to the bowel in high-grade serous ovarian cancer (OC) and evaluate their associations with clinical outcomes.

Methods: We performed RNA sequencing of OC primary tumors (PTs) and their corresponding bowel metastases (n = 21 discovery set; n = 18 replication set). Differentially expressed genes (DEGs) were those expressed at least 2-fold higher in bowel metastases (BMets) than PTs in at least 30% of patients (P < .

MicroRNA-21 induces loss of 15-hydroxyprostaglandin dehydrogenase in early gastric tubular adenocarcinoma.

15-hydroxyprostaglandin dehydrogenase (15-PGDH), the rate-limiting enzyme in prostaglandin E2 degradation, is decreased in gastric cancers and microRNA (miR)-21 is one of the regulators. We investigated the expression and regulation of 15-PGDH in eary gastric carcinogenesis utilizing endoscopic submucosal dissection (ESD) and gastric cancer cell lines. Expression of 15-PGDH and cyclooxygenase-2 as well as the promoter methylation of 15-PGDH were evaluted.

Therapeutic targeting of PFKFB3 with a novel glycolytic inhibitor PFK158 promotes lipophagy and chemosensitivity in gynecologic cancers.

Metabolic alterations are increasingly recognized as important novel anti-cancer targets. Among several regulators of metabolic alterations, fructose 2,6 bisphosphate (F2,6BP) is a critical glycolytic regulator. Inhibition of the active form of PFKFB3 using a novel inhibitor, PFK158 resulted in reduced glucose uptake, ATP production, lactate release as well as induction of apoptosis in gynecologic cancer cells.

Zinc finger protein 746 promotes colorectal cancer progression via c-Myc stability mediated by glycogen synthase kinase 3β and F-box and WD repeat domain-containing 7.

To elucidate the underlying oncogenic mechanism of zinc finger protein 746 (ZNF746), current study was conducted in colorectal cancers (CRCs). Herein, ZNF746 was overexpressed in HCT116, SW620, and SW480 cells, which was supported by CRC tissue microarray and TCGA analysis. Also, DNA microarray revealed the differentially expressed gene profile particularly related to cell cycle genes and c-Myc in ZNF746 depleted HCT116 cells.

Quinacrine upregulates p21/p27 independent of p53 through autophagy-mediated downregulation of p62-Skp2 axis in ovarian cancer.

We have previously shown that the anti-malarial compound Quinacrine (QC) inhibits ovarian cancer (OC) growth by modulating autophagy. In the present study we extended these studies to identify the molecular pathways regulated by QC to promote apoptosis independent of p53 status in OC. QC exhibited strong anti-cancer properties in OC cell lines in contrast to other anti-malarial autophagy inhibiting drugs.

CNOT2 promotes proliferation and angiogenesis via VEGF signaling in MDA-MB-231 breast cancer cells.

Here the underlying role of CNOT2, a subunit of CCR4-NOT complex, was elucidated in cancer progression. CNOT2 was overexpressed in HIT-T15, ASPC-1, BXPC-3, PC-3, LNCaP, MCF-7 and MDA-MB-231 cell lines, which was confirmed by Tissue array in various human tumor tissues. Also, CNOT2 depletion suppressed proliferation and colony formation of MDA-MB-231 cells.

Loss of HSulf-1: The Missing Link between Autophagy and Lipid Droplets in Ovarian Cancer.

Defective autophagy and deranged metabolic pathways are common in cancer; pharmacologic targeting of these two pathways could provide a viable therapeutic option. However, how these pathways are regulated by limited availability of growth factors is still unknown. Our study shows that HSulf-1 (endosulfatase), a known tumor suppressor which attenuates heparin sulfate binding growth factor signaling, also regulates interplay between autophagy and lipogenesis.

Decursin enhances TRAIL-induced apoptosis through oxidative stress mediated- endoplasmic reticulum stress signalling in non-small cell lung cancers.

Background And Purpose: The TNF-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent due to its remarkable ability to selectively kill tumour cells. However, because most tumours exhibit resistance to TRAIL-induced apoptosis, the development of combination therapies to overcome resistance to TRAIL is required for effective cancer therapy.

Experimental Approach: Cell viability and possible synergy between the plant pyranocoumarin decursin and TRAIL was measured by MTT assay and calcusyn software.

CCR4-NOT2 Promotes the Differentiation and Lipogenesis of 3T3-L1 Adipocytes via Upregulation of PPARx03B3;, CEBPα and Inhibition of P-GSK3α/β and β-Catenin.

Background/aims: Though CCR4-NOT2 (CNOT2), one of CCR4-NOT complex subunits, was known to be involved in metastasis and apoptosis through transcription and mRNA degradation, its other biological function is poorly understood so far. The aim of this study is to elucidate the molecular role of CNOT2 in the differentiation process of 3T3-L1 preadipocytes.

Methods And Results: CNOT2 was overexpressed during the differentiation process of 3T3-L1 preadipocytes.

Apoptotic Effect of Sanggenol L via Caspase Activation and Inhibition of NF-κB Signaling in Ovarian Cancer Cells.

In the present study, the underlying apoptotic mechanism of sanggenol L was elucidated in ovarian cancer cells. Sanggenol L showed cytotoxic and antiproliferative effect in A2780, SKOV-3, and OVCAR-3 ovarian cancer cells in a concentration-dependent fashion. Consistently, sanggenol L increased sub-G1 phase population and early and late apoptotic portion in ovarian cancer cells.

Inhibition of Myeloid Cell Leukemia 1 and Activation of Caspases Are Critically Involved in Gallotannin-induced Apoptosis in Prostate Cancer Cells.

Although gallotannin contained in several medicinal plants was known to have multi-biological activities, such as antioxidant, antiinflammatory, antimicrobial, immunomodulatory, and antitumor effects, the underlying apoptotic mechanism of gallotannin is not fully understood so far. Thus, in the present study, the apoptotic mechanism of gallotannin was elucidated in DU145, PC-3, and M2182 prostate cancer cells in association with myeloid cell leukemia 1 (Mcl-1) signaling. Gallotannin exerted dose-dependent cytotoxicity in DU145, PC-3, and M2182 prostate cancer cells.

Activation of Caspase-9/3 and Inhibition of Epithelial Mesenchymal Transition are Critically Involved in Antitumor Effect of Phytol in Hepatocellular Carcinoma Cells.

This study was designed to investigate the antitumor mechanism of Phytol in hepatocellular carcinomas including Huh7 and HepG2 cells in association with caspase dependent apoptosis and epithelial mesenchymal transition (EMT) signaling. Phytol significantly suppressed the viability of Huh7 and HepG2 cells. Also, Phytol significantly increased the sub G1 population and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling (TUNEL) positive cells in a concentration dependent manner in Huh7 and HepG2 cells.

A derivative of epigallocatechin-3-gallate induces apoptosis via SHP-1-mediated suppression of BCR-ABL and STAT3 signalling in chronic myelogenous leukaemia.

Background And Purpose: Epigallocatechin-3-gallate (EGCG) is a component of green tea known to have chemo-preventative effects on several cancers. However, EGCG has limited clinical application, which necessitates the development of a more effective EGCG prodrug as an anticancer agent.

Experimental Approach: Derivatives of EGCG were evaluated for their stability and anti-tumour activity in human chronic myeloid leukaemia (CML) K562 and KBM5 cells.

Apoptotic Effect of Galbanic Acid via Activation of Caspases and Inhibition of Mcl-1 in H460 Non-Small Lung Carcinoma Cells.

Galbanic acid (GBA), a major compound of Ferula assafoetida, was known to have cytotoxic, anti-angiogenic and apoptotic effects in prostate cancer and murine Lewis lung cancer cells; the underling apoptotic mechanism of GBA still remains unclear so far. Thus, in the present study, the apoptotic mechanism of GBA was investigated mainly in H460 non-small cell lung carcinoma (NSCLC) cells because H460 cells were most susceptible to GBA than A549, PC-9 and HCC827 NSCLC cells. Galbanic acid showed cytotoxicity in wild EGFR type H460 and A549 cells better than other mutant type PC-9 and HCC827 NSCLC cells.

The heparan sulfate mimetic PG545 interferes with Wnt/β-catenin signaling and significantly suppresses pancreatic tumorigenesis alone and in combination with gemcitabine.

The heparan sulfate mimetic PG545 has been shown to exert anti-angiogenic and anti-metastatic activity in vitro and in vivo cancer models. Although much of this activity has been attributed to inhibition of heparanase and heparan sulfate-binding growth factors, it was hypothesized that PG545 may additionally disrupt Wnt signaling, an important pathway underlying the malignancy of pancreatic cancer. We show that PG545, by directly interacting with Wnt3a and Wnt7a, inhibits Wnt/β-catenin signaling leading to inhibition of proliferation in pancreatic tumor cell lines.

Loss of HSulf-1 promotes altered lipid metabolism in ovarian cancer.

Background: Loss of the endosulfatase HSulf-1 is common in ovarian cancer, upregulates heparin binding growth factor signaling and potentiates tumorigenesis and angiogenesis. However, metabolic differences between isogenic cells with and without HSulf-1 have not been characterized upon HSulf-1 suppression in vitro. Since growth factor signaling is closely tied to metabolic alterations, we determined the extent to which HSulf-1 loss affects cancer cell metabolism.

Erratum to: Loss of HSulf-1 promotes altered lipid metabolism in ovarian cancer.

[This corrects the article DOI: 10.1186/2049-3002-2-13.].

Regulation of crosstalk between epithelial to mesenchymal transition molecules and MMP-9 mediates the antimetastatic activity of anethole in DU145 prostate cancer cells.

The underlying antimetastatic mechanism of anethole (1) still remains unclear in association with the molecules of the epithelial to mesenchymal transition (EMT). Herein, the role of the EMT molecules was elucidated in terms of the antimetastatic activity of 1 using DU145 cells. Anethole significantly inhibited the adhesion of DU145 cells to vitronectin-coated plates, as well as migration in a wound-healing assay and invasion using a Boyden chamber.

Inactivation of HDAC3 and STAT3 is critically involved in 1-stearoyl-sn-glycero-3-phosphocholine-induced apoptosis in chronic myelogenous leukemia K562 cells.

We here investigated the anticancer mechanism of 1-stearoyl-sn-glycero-3-phosphocholine (LPC), one of the lysophosphatidylcholines, in chronic myelogenous leukemia (CML) K562 cells. LPC significantly showed cytotoxicity at 80 μM and induced apoptosis by sub-G1 accumulation, increase in Annexin V positive and caspase activation. LPC enhanced histone H3 acetylation but decreased histone deacetylase (HDAC) activity and HDAC3 expression.