Overexpression of Fatty Acid Synthase Upregulates Glutamine-Fructose-6-Phosphate Transaminase 1 and O-Linked N-Acetylglucosamine Transferase to Increase O-GlcNAc Protein Glycosylation and Promote Colorectal Cancer Growth.

Fatty acid synthesis has been extensively investigated as a therapeutic target in cancers, including colorectal cancer (CRC). Fatty acid synthase (FASN), a key enzyme of de novo lipid synthesis, is significantly upregulated in CRC, and therapeutic approaches of targeting this enzyme are currently being tested in multiple clinical trials. However, the mechanisms behind the pro-oncogenic action of FASN are still not completely understood.

Upregulation of CD36, a Fatty Acid Translocase, Promotes Colorectal Cancer Metastasis by Increasing MMP28 and Decreasing E-Cadherin Expression.

Altered fatty acid metabolism continues to be an attractive target for therapeutic intervention in cancer. We previously found that colorectal cancer (CRC) cells with a higher metastatic potential express a higher level of fatty acid translocase (CD36). However, the role of CD36 in CRC metastasis has not been studied.

Novel chemotherapeutic agent, FND-4b, activates AMPK and inhibits colorectal cancer cell proliferation.

Colorectal cancer (CRC) is the second leading cause of cancer deaths in the US with the majority of deaths due to metastatic disease. Current chemotherapeutic regimens involve highly toxic agents, which limits their utility; therefore, more effective and less toxic agents are required to see a reduction in CRC mortality. Novel fluorinated N,N'-diarylureas (FND) were developed and characterized by our group as potent activators of adenosine monophosphate-activated kinase (AMPK) that inhibit cell cycle progression.

Membrane associated collagen XIII promotes cancer metastasis and enhances anoikis resistance.

Background: Increased collagen expression and deposition are associated with cancer progression and poor prognosis in breast cancer patients. However, function and regulation of membrane-associated collagen in breast cancer have not been determined. Collagen XIII is a type II transmembrane protein within the collagen superfamily.

Development of murine bariatric surgery models: lessons learned.

Roux-en-Y gastric bypass (RYGB) improves comorbidities such as diabetes and hypertension and lowers the risk of obesity-related cancers. To better understand the physiologic and genetic influences of bariatric surgery, a reliable murine model is needed that can be extended to genetically engineered mice. Given the complexity of these procedures, few researchers have successfully implemented these techniques beyond larger rodent models.

Preclinical evaluation of novel fatty acid synthase inhibitors in primary colorectal cancer cells and a patient-derived xenograft model of colorectal cancer.

Fatty Acid Synthase (FASN), a key enzyme of lipogenesis, is upregulated in many cancers including colorectal cancer (CRC); increased FASN expression is associated with poor prognosis. Potent FASN inhibitors (TVBs) developed by 3-V Biosciences demonstrate anti-tumor activity and and a favorable tolerability profile in a Phase I clinical trial. However, CRC characteristics associated with responsiveness to FASN inhibition are not fully understood.

The role of ROS generation from magnetic nanoparticles in an alternating magnetic field on cytotoxicity.

Unlabelled: Monosaccharide coated iron oxide nanoparticles were developed to selectively target colon cancer cell lines for magnetically mediated energy delivery therapy. The nanoparticles were prepared using a coupling reaction to attach the glucose functional group to the iron oxide core, and functionality was confirmed with physicochemical characterization techniques. The targeted nanoparticles were internalized into CT26 cells at a greater extent than non-targeted nanoparticles, and the nanoparticles were shown to be localized within lysosomes.

RNA Nanoparticles Derived from Three-Way Junction of Phi29 Motor pRNA Are Resistant to I-125 and Cs-131 Radiation.

Radiation reagents that specifically target tumors are in high demand for the treatment of cancer. The emerging field of RNA nanotechnology might provide new opportunities for targeted radiation therapy. This study investigates whether chemically modified RNA nanoparticles derived from the packaging RNA (pRNA) three-way junction (3WJ) of phi29 DNA-packaging motor are resistant to potent I-125 and Cs-131 radiation, which is a prerequisite for utilizing these RNA nanoparticles as carriers for targeted radiation therapy.

Prolyl-4-hydroxylase α subunit 2 promotes breast cancer progression and metastasis by regulating collagen deposition.

Background: Increased collagen deposition provides physical and biochemical signals to support tumor growth and invasion during breast cancer development. Therefore, inhibition of collagen synthesis and deposition has been considered a strategy to suppress breast cancer progression. Collagen prolyl-4-hydroxylase α subunit 2 (P4HA2), an enzyme hydroxylating proline residues in -X-Pro-Gly- sequences, is a potential therapeutic target for the disorders associated with increased collagen deposition.

Engineered nanopore of Phi29 DNA-packaging motor for real-time detection of single colon cancer specific antibody in serum.

The ingenious design of the bacterial virus phi29 DNA packaging nanomotor with an elegant and elaborate channel has inspired its application for single molecule detection of antigen/antibody interactions. The hub of this bacterial virus nanomotor is a truncated cone-shaped connector consisting of 12 protein subunits. These subunits form a ring with a central 3.

Murine portal vein catheterization to analyze liver-directed therapies.

Background: Small interfering RNA (siRNA) provides a highly selective method to target mutated pathways; however, its use is complicated by specific delivery to tumor cells. The aims of the present study were to develop a novel murine model of portal vein catheterization for the chronic delivery of therapeutic agents to liver metastases, determine the benefits of local delivery of siRNA to liver metastases, and determine the utility of epithelial cell adhesion molecule (EpCAM) as a selective target for siRNA delivery to colorectal cancer (CRC) metastases.

Materials And Methods: First, portal vein catheterization was performed through a midline laparotomy in 2 mo-old Balb/C mice.

Deregulation of Wnt/β-catenin signaling through genetic or epigenetic alterations in human neuroendocrine tumors.

Carcinoid tumors are rare neuroendocrine tumors (NETs) that are increasing in incidence. Mutation and altered expression of Wnt/β-catenin signaling components have been described in many tumors but have not been well-studied in NETs. Here, we observed accumulation of β-catenin in the cytoplasm and/or nucleus in 25% of clinical NET tissues.

Ultrastable synergistic tetravalent RNA nanoparticles for targeting to cancers.

One of the advantages of nanotechnology is the feasibility to construct therapeutic particles carrying multiple therapeutics with defined structure and stoichiometry. The field of RNA nanotechnology is emerging. However, controlled assembly of stable RNA nanoparticles with multiple functionalities which retain their original role is challenging due to refolding after fusion.

Novel small interfering RNA cotargeting strategy as treatment for colorectal cancer.

Background: RNA interference has the potential to be more selective than small molecule inhibitors and can be used to target proteins, such as Ras, that are currently undruggable. The purpose of our study was to determine the optimal cotargeting strategy of the commonly mutated PI3K/AKT/mTOR and Ras pathways by a selective RNA interference approach in colorectal cancer cell lines possessing coexistent PIK3CA and KRAS mutations.

Methods: Human colorectal cancer cell lines HCT116 and DLD-1 were treated with a panel of small interfering RNAs directed against the PI3K/AKT/mTOR and Ras pathways; proliferation, apoptosis, and protein expression were assessed.

G9a interacts with Snail and is critical for Snail-mediated E-cadherin repression in human breast cancer.

Breast cancers are highly heterogeneous but can be grouped into subtypes based on several criteria, including level of expression of certain markers. Claudin-low breast cancer (CLBC) is associated with early metastasis and resistance to chemotherapy, while gene profiling indicates it is characterized by the expression of markers of epithelial-mesenchymal transition (EMT) - a phenotypic conversion linked with metastasis. Although the epigenetic program controlling the phenotypic and cellular plasticity of EMT remains unclear, one contributor may be methylation of the E-cadherin promoter, resulting in decreased E-cadherin expression, a hallmark of EMT.

Inhibition of fatty acid synthase attenuates CD44-associated signaling and reduces metastasis in colorectal cancer.

Fatty acid synthase (FASN) and ATP-citrate lyase, key enzymes of de novo lipogenesis, are significantly upregulated and activated in many cancers and portend poor prognosis. Even though the role of lipogenesis in providing proliferative and survival advantages to cancer cells has been described, the impact of aberrant activation of lipogenic enzymes on cancer progression remains unknown. In this study, we found that elevated expression of FASN is associated with advanced stages of colorectal cancer (CRC) and liver metastasis, suggesting that it may play a role in progression of CRC to metastatic disease.

Inhibition of aldose reductase prevents colon cancer metastasis.

Colon cancer is the third most common cause of cancer and is the second leading cause of cancer deaths in the USA. Although inhibition of aldose reductase (AR) is known to prevent human colon cancer cell growth in nude mice xenografts, the role of AR in the regulation of cancer metastasis is not known. We now demonstrate the mechanisms by which AR regulates colon cancer metastasis in vitro and in vivo.

mTORC1 and mTORC2 regulate EMT, motility, and metastasis of colorectal cancer via RhoA and Rac1 signaling pathways.

Activation of phosphoinositide 3-kinase (PI3K)/Akt signaling is associated with growth and progression of colorectal cancer (CRC). We have previously shown that the mTOR kinase, a downstream effector of PI3K/Akt signaling, regulates tumorigenesis of CRC. However, the contribution of mTOR and its interaction partners toward regulating CRC progression and metastasis remains poorly understood.

The role of neurotensin in physiologic and pathologic processes.

Purpose Of Review: Neurotensin is a 13-amino acid peptide found in the central nervous system central nervous system and the gastrointestinal tract. Since its initial discovery in 1973, neurotensin has been shown to play a role in a wide range of physiologic and pathologic processes throughout the body. Ongoing research efforts continue to clarify the role of neurotensin in various central nervous system and gastrointestinal processes, as well as how disruption of these normal mechanisms may lead to diseases ranging from schizophrenia to colorectal cancer.

VEGFR-2 expression in carcinoid cancer cells and its role in tumor growth and metastasis.

Carcinoid tumors are slow growing and highly vascular neuroendocrine neoplasms that are increasing in incidence. Previously, we showed that carcinoid tumors express vascular endothelial growth factor receptor 2 (VEGFR-2) in the epithelial compartment of carcinoid tumor sections; yet, its role is not completely understood. The purpose of our study was to: (i) assess the expression of VEGFR-2 in the novel human carcinoid cell line BON, (ii) to determine the role of PI3K/Akt signaling on VEGFR-2 expression and (iii) to assess the effect of VEGFR-2 on BON cell invasion, migration and proliferation.

Novel expression patterns of PI3K/Akt/mTOR signaling pathway components in colorectal cancer.

Background: The phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway plays a critical role in the growth and progression of colorectal cancer (CRC). The purpose of our study was 2-fold: (1) to determine the expression levels of several key components of this pathway, including p85alpha, Akt1, Akt2, p-mTOR(Ser2448), and p-p70S6K(Thr389) in CRCs; and (2) to correlate the expression of these proteins with cancer stage and location (left versus right side).

Study Design: Immunohistochemistry for p85alpha, Akt1, Akt2, p-mTOR(Ser2448), and p-p70S6K(Thr389) was performed on normal colon and CRCs from 154 patients.

Hydrodynamic delivery protocols.

RNA interference (RNAi) holds considerable promise as a novel therapeutic strategy to silence disease-causing genes not amenable to conventional therapeutics. Since it relies on small interfering RNAs (siRNAs), which are the mediators of RNAi-induced specific mRNA degradation, a major issue is the delivery of therapeutically active siRNAs into the target tissue. In vivo gene silencing with RNAi has been reported using both viral vector delivery and high-pressure, high-volume intravenous (i.

PTEN loss induces epithelial--mesenchymal transition in human colon cancer cells.

Background: The epithelial-mesenchymal transition is a critical early event in the invasion and metastasis of many types of cancer, including colorectal cancer (CRC). Chronic inflammation is an inducer of several cancer types and inflammatory cytokines have been implicated in tumor invasion.

Materials And Methods: Human colon cancer cell lines HCT116 and SW480 were transfected with phosphatase and tensin homolog deleted on chromosome 10 (PTEN) siRNA or non-targeting control (NTC).

Targeted inhibition of mammalian target of rapamycin signaling inhibits tumorigenesis of colorectal cancer.

Purpose: The mammalian target of rapamycin (mTOR) kinase acts downstream of phosphoinositide 3-kinase/Akt to regulate cellular growth, metabolism, and cytoskeleton. Because approximately 60% of sporadic colorectal cancers (CRC) exhibit high levels of activated Akt, we determined whether downstream mTOR signaling pathway components are overexpressed and activated in CRCs.

Experimental Design: HCT116, KM20, Caco-2, and SW480 human CRC cells were used to determine the effects of pharmacologic (using rapamycin) or genetic (using RNAi) blockade of mTOR signaling on cell proliferation, apoptosis, cell cycle progression, and subcutaneous growth in vivo.