Simultaneous Activation of Induced Heterodimerization between CXCR4 Chemokine Receptor and Cannabinoid Receptor 2 (CB2) Reveals a Mechanism for Regulation of Tumor Progression.

The G-protein-coupled chemokine receptor CXCR4 generates signals that lead to cell migration, cell proliferation, and other survival mechanisms that result in the metastatic spread of primary tumor cells to distal organs. Numerous studies have demonstrated that CXCR4 can form homodimers or can heterodimerize with other G-protein-coupled receptors to form receptor complexes that can amplify or decrease the signaling capacity of each individual receptor. Using biophysical and biochemical approaches, we found that CXCR4 can form an induced heterodimer with cannabinoid receptor 2 (CB2) in human breast and prostate cancer cells.

Germ line variants of human N-methylpurine DNA glycosylase show impaired DNA repair activity and facilitate 1,N6-ethenoadenine-induced mutations.

Human N-methylpurine DNA glycosylase (hMPG) initiates base excision repair of a number of structurally diverse purine bases including 1,N(6)-ethenoadenine, hypoxanthine, and alkylation adducts in DNA. Genetic studies discovered at least eight validated non-synonymous single nucleotide polymorphisms (nsSNPs) of the hMPG gene in human populations that result in specific single amino acid substitutions. In this study, we tested the functional consequences of these nsSNPs of hMPG.

Downstream of mutant KRAS, the transcription regulator YAP is essential for neoplastic progression to pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with poor survival rates and frequently carries oncogenic KRAS mutation. However, KRAS has thus far not been a viable therapeutic target. We found that the abundance of YAP mRNA, which encodes Yes-associated protein (YAP), a protein regulated by the Hippo pathway during tissue development and homeostasis, was increased in human PDAC tissue compared with that in normal pancreatic epithelia.

ROS-mediated regulation of CXCR4 in cancer.

Oxidative stress and the accumulation of reactive oxygen species (ROS) play a role in cancer cells developing an advanced, phenotypic signature that associates with metastasis and progression. Increased ROS concentrations are involved in promoting cancer development and metastasis by inducing expression of oncogenes, suppressing activity of anti-survival molecules and by activating various cell survival and proliferation signaling pathways. Oxidative stress is higher in the epithelium of cancer patients than patients without the disease, and antioxidant trials are currently being explored as a therapeutic option.

Cysteine (C)-X-C Receptor 4 Regulates NADPH Oxidase-2 During Oxidative Stress in Prostate Cancer Cells.

Reactive oxygen species (ROS) are implicated in many human diseases, including cancer. We have previously demonstrated that ROS increased the expression and activity of the chemokine receptor, CXCR4, which enhanced metastatic functions in prostate cancer cells. Studies have also revealed that CXCR4 and its ligand, SDF-1α, promoted ROS accumulation; however the source of ROS was not investigated.

Cysteine (C)-x-C receptor 4 undergoes transportin 1-dependent nuclear localization and remains functional at the nucleus of metastatic prostate cancer cells.

The G-protein coupled receptor (GPCR), Cysteine (C)-X-C Receptor 4 (CXCR4), plays an important role in prostate cancer metastasis. CXCR4 is generally regarded as a plasma membrane receptor where it transmits signals that support transformation, progression and eventual metastasis. Due to the central role of CXCR4 in tumorigenesis, therapeutics approaches such as antagonist and monoclonal antibodies have focused on receptors that exist on the plasma membrane.

ROS-mediated activation of AKT induces apoptosis via pVHL in prostate cancer cells.

Reactive oxygen species (ROS) play a central role in oxidative stress, which leads to the onset of diseases, such as cancer. Furthermore, ROS contributes to the delicate balance between tumor cell survival and death. However, the mechanisms by which tumor cells decide to elicit survival or death signals during oxidative stress are not completely understood.

The phytoalexin camalexin mediates cytotoxicity towards aggressive prostate cancer cells via reactive oxygen species.

Camalexin is a phytoalexin that accumulates in various cruciferous plants upon exposure to environmental stress and plant pathogens. Besides moderate antibacterial and antifungal activity, camalexin was reported to also exhibit antiproliferative and cancer chemopreventive effects in breast cancer and leukemia. We studied the cytotoxic effects of camalexin treatment on prostate cancer cell lines and whether this was mediated by reactive oxygen species (ROS) generation.

PTEN regulation of ERK1/2 signaling in cancer.

Since its discovery, the tumor suppressor phosphatase and tensin homolog (PTEN) has become a molecule with a wide spectrum of functions, which is typically meditated through its lipid phosphatase activity; however, PTEN also functions in a phosphatase-independent manner. It is well established that PTEN regulates several signaling pathways, such as phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT), janus kinase (JAK)/signal transducers and activators of transcription (STAT), focal adhesion kinase (FAK), and more recent, extracellular signal-regulated kinase (ERK)1/2, where activation of these pathways typically leads to cancer development and progression. In regard to most of these pathways, the underlining molecular mechanism of PTEN-mediated regulation is well established, but not so much for the ERK1/2 pathway.

ROS enhances CXCR4-mediated functions through inactivation of PTEN in prostate cancer cells.

Inactivation of the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is heavily implicated in the tumorigenesis of prostate cancer. Conversely, the upregulation of the chemokine (CXC) receptor 4 (CXCR4) is associated with prostate cancer progression and metastasis. Studies have shown that loss of PTEN permits CXCR4-mediated functions in prostate cancer cells.

Loss of PTEN permits CXCR4-mediated tumorigenesis through ERK1/2 in prostate cancer cells.

Loss of PTEN is frequently observed in androgen-independent prostate cancer, resulting in the deregulation of metastatic events. SDF1α activation of CXCR4 induces signaling pathways that have been implicated in prostate metastasis and progression to an advanced disease. The pathways of CXCR4 and PTEN converge, leading to the promotion and regulation of tumorigenesis, respectively.