Targeting dysregulated lipid metabolism in the tumor microenvironment.

The reprogramming of lipid metabolism and its association with oncogenic signaling pathways within the tumor microenvironment (TME) have emerged as significant hallmarks of cancer. Lipid metabolism is defined as a complex set of molecular processes including lipid uptake, synthesis, transport, and degradation. The dysregulation of lipid metabolism is affected by enzymes and signaling molecules directly or indirectly involved in the lipid metabolic process.

The role of myokines in cancer: crosstalk between skeletal muscle and tumor.

Loss of skeletal muscle mass is a primary feature of sarcopenia and cancer cachexia. In cancer patients, tumor-derived inflammatory factors promote muscle atrophy via tumor-to-muscle effects, which is closely associated with poor prognosis. During the past decade, skeletal muscle has been considered to function as an autocrine, paracrine, and endocrine organ by releasing numerous myokines.

IKKα-deficient lung adenocarcinomas generate an immunosuppressive microenvironment by overproducing Treg-inducing cytokines.

The tumor microenvironment (TME) provides potential targets for cancer therapy. However, how signals originating in cancer cells affect tumor-directed immunity is largely unknown. Deletions in the locus, coding for IκB kinase α (IKKα), correlate with reduced lung adenocarcinoma (ADC) patient survival and promote Kras-initiated ADC development in mice, but it is unknown how reduced IKKα expression affects the TME.

Direct Contact with Platelets Induces Podoplanin Expression and Invasion in Human Oral Squamous Cell Carcinoma Cells.

Oral squamous cell carcinoma (OSCC) is mostly diagnosed at an advanced stage, with local and/or distal metastasis. Thus, locoregional and/or local control of the primary tumor is crucial for a better prognosis in patients with OSCC. Platelets have long been considered major players in cancer metastasis.

Platelet CLEC2-Podoplanin Axis as a Promising Target for Oral Cancer Treatment.

Cancer tissues are not just simple masses of malignant cells, but rather complex and heterogeneous collections of cellular and even non-cellular components, such as endothelial cells, stromal cells, immune cells, and collagens, referred to as tumor microenvironment (TME). These multiple players in the TME develop dynamic interactions with each other, which determines the characteristics of the tumor. Platelets are the smallest cells in the bloodstream and primarily regulate blood coagulation and hemostasis.

JNK-mediated Ser27 phosphorylation and stabilization of SIRT1 promote growth and progression of colon cancer through deacetylation-dependent activation of Snail.

Sirtuin 1 (SIRT1), an NAD -dependent histone/protein deacetylase, has multifaceted functions in various biological events such as inflammation, aging, and energy metabolism. The role of SIRT1 in carcinogenesis, however, is still under debate. Recent studies have indicated that aberrant overexpression of SIRT1 is correlated with metastasis and poor prognosis in several types of malignancy, including colorectal cancer.

IL-1β induces expression of proinflammatory cytokines and migration of human colon cancer cells through upregulation of SIRT1.

SIRT1 is a mammalian NAD-dependent deacetylase, which is known to be involved in various physiological events, such as adaptive response to environmental stresses including caloric restriction, as well as in aging and cellular senescence. However, recent studies have revealed overexpression of SIRT1 in many different types of human malignancies, particularly colon cancer. Interleukin-1β (IL-1β) is a proinflammatory cytokine that plays a major role in invasiveness, stemness and progression of colon cancer.

STAT3 Stabilizes IKKα Protein through Direct Interaction in Transformed and Cancerous Human Breast Epithelial Cells.

Signal transducer and activator of transcription 3 (STAT3) and nuclear factor-κB (NF-κB) are two representative transcription factors that play a critical role in inflammation-associated tumorigenesis through multi-level cooperation. Unlike other types of tumors, breast carcinomas have shown a significant dependency on the non-classical NF-κB pathway as well as the classical one. The α subunit of the inhibitor of the κB kinase (IKK) complex, IKKα, is involved in both classical and non-classical activation of NF-κB.

Thymoquinone Suppresses Migration of Human Renal Carcinoma Caki-1 Cells through Inhibition of the PGE-Mediated Activation of the EP2 Receptor Pathway.

Renal cell carcinoma (RCC) is likely to metastasize to other organs, and is often resistant to conventional chemotherapies. Thymoquinone (TQ), a phytochemical derived from the seeds of , has been shown to inhibit migration and metastasis in various cancers. In this study, we assessed the effect of TQ on the migratory activity of human RCC Caki-1 cells.

Chemerin Treatment Inhibits the Growth and Bone Invasion of Breast Cancer Cells.

Chemerin is secreted as prochemerin from various cell types and then cleaved into the bioactive isoform by specific proteases. In various cancer types, chemerin exhibits pro- or antitumor effects. In the present study, chemerin treatment significantly inhibited the viability and invasion of breast cancer cells in the absence or presence of transforming growth factor (TGF)-β and insulin-like growth factor (IGF)-1.

ERK Dephosphorylation through MKP1 Deacetylation by SIRT1 Attenuates RAS-Driven Tumorigenesis.

The role of Situin 1 (SIRT1) in tumorigenesis is still controversial due to its wide range of substrates, including both oncoproteins and tumor suppressors. A recent study has demonstrated that SIRT1 interferes in the Kirsten rat sarcoma viral oncogene homolog (KRAS)-driven activation of the Raf-mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK pathway, thereby inhibiting tumorigenesis. However, the molecular mechanism of SIRT1 as a tumor suppressor in RAS-driven tumorigenesis has been less clearly determined.

Thymoquinone induces apoptosis of human renal carcinoma Caki-1 cells by inhibiting JAK2/STAT3 through pro-oxidant effect.

Currently, there are limited effective treatment options for renal cell carcinoma (RCC), due to its poor responses to conventional therapies. Instead of using extrinsic anti-cancer drugs, cancer cell-intrinsic reactive oxygen species (ROS) can be a weapon of RCC treatment. In the present study, we found that the phytochemical thymoquinone (TQ), a bioactive natural product obtained from the black cumin seeds of Nigella sativa, generates intracellular ROS in human renal cancer Caki-1 cells.

CCL28-induced RARβ expression inhibits oral squamous cell carcinoma bone invasion.

Oral squamous cell carcinoma (OSCC) frequently invades the maxillary or mandibular bone, and this bone invasion is closely associated with poor prognosis and survival. Here, we show that CCL28 functions as a negative regulator of OSCC bone invasion. CCL28 inhibited invasion and epithelial-mesenchymal transition (EMT), and its inhibition of EMT was characterized by induced E-cadherin expression and reduced nuclear localization of β-catenin in OSCC cells with detectable RUNX3 expression levels.

Large-scale pharmacogenomics based drug discovery for ITGB3 dependent chemoresistance in mesenchymal lung cancer.

Even when targets responsible for chemoresistance are identified, drug development is often hampered due to the poor druggability of these proteins. We systematically analyzed therapy-resistance with a large-scale cancer cell transcriptome and drug-response datasets and predicted the candidate drugs based on the gene expression profile. Our results implicated the epithelial-mesenchymal transition as a common mechanism underlying resistance to chemotherapeutic drugs.

Curcumin suppresses oncogenicity of human colon cancer cells by covalently modifying the cysteine 67 residue of SIRT1.

SIRT1, an NAD-dependent histone/protein deacetylase, has diverse physiological actions. Recent studies have demonstrated that SIRT1 is overexpressed in colorectal cancer, suggesting its oncogenic potential. However, the molecular mechanisms by which overexpressed SIRT1 induces the progression of colorectal cancer and its inhibition remain largely unknown.

Leptin induces SIRT1 expression through activation of NF-E2-related factor 2: Implications for obesity-associated colon carcinogenesis.

Leptin, a representative adipokine secreted from the white adipose tissue, is considered as a potential linker between obesity and cancer. SIRT1 is an NAD-dependent histone/protein deacetylase speculated to function as an oncogene. In the present study, we found that leptin signaling-defective ob/ob and db/db mice had lower colonic expression of SIRT1 compared with leptin signaling-intact C57BL/6J mice, implying that leptin signaling is crucial for SIRT1 expression in vivo.

IKKα inactivation promotes Kras-initiated lung adenocarcinoma development through disrupting major redox regulatory pathways.

Lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC) are two distinct and predominant types of human lung cancer. IκB kinase α (IKKα) has been shown to suppress lung SCC development, but its role in ADC is unknown. We found inactivating mutations and homologous or hemizygous deletions in the locus, which encodes IKKα, in human lung ADCs.

Autoreactive T Cells and Chronic Fungal Infection Drive Esophageal Carcinogenesis.

Humans with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a T cell-driven autoimmune disease caused by impaired central tolerance, are susceptible to chronic fungal infection and esophageal squamous cell carcinoma (ESCC). However, the relationship between autoreactive T cells and chronic fungal infection in ESCC development remains unclear. We find that kinase-dead Ikkα knockin mice develop APECED-like phenotypes, including impaired central tolerance, autoreactive T cells, chronic fungal infection, and ESCCs expressing specific human ESCC markers.

15-Deoxy-Δ-prostaglandin J stabilizes hypoxia inducible factor-1α through induction of heme oxygenase-1 and direct modification ofprolyl-4-hydroxylase 2.

15-Deoxy-Δ-prostaglandin J (15d-PGJ), a representative J-series cyclopentenone prostaglandin, has biphasic roles in cell proliferation and apoptosis. Hypoxia inducible factor-1 (HIF-1) regulates expression of various genes involved in tumor growth and angiogenesis. In the present study, treatment of human breast cancer (MCF-7) cells with 15d-PGJ resulted in the accumulation of the α-subunit of HIF-1.

TNFR2 expression by CD4 effector T cells is required to induce full-fledged experimental colitis.

There is now compelling evidence that TNFR2 is constitutively expressed on CD4(+) Foxp3(+) regulatory T cells (Tregs) and TNF-TNFR2 interaction is critical for the activation, expansion and functional stability of Tregs. However, we showed that the expression of TNFR2 was also up-regulated on CD4(+) Foxp3(-) effector T cells (Teffs) upon TCR stimulation. In order to define the role of TNFR2 in the pathogenic CD4 T cells, we compared the effect of transferred naïve CD4 cells from WT mice and TNFR2(-/-) mice into Rag 1(-/-) recipients.

Isolation and Bioactivity Analysis of Ethyl Acetate Extract from Acer tegmentosum Using In Vitro Assay and On-Line Screening HPLC-ABTS(+) System.

The Acer tegmentosum (3 kg) was extracted using hot water, and the freeze-dried extract powder was partitioned successively using dichloromethane (DCM), ethyl acetate (EA), butyl alcohol (n-BuOH), and water. From the EA extract fraction (1.24 g), five phenolic compounds were isolated by the silica gel, octadecyl silica gel, and Sephadex LH-20 column chromatography.