The deubiquitinase USP10 protects pancreatic cancer cells from endoplasmic reticulum stress.

The ubiquitin-specific peptidase 10 (USP10) plays a context-specific, pro or anti-tumorigenic role in different malignancies. However, the role of USP10 in pancreatic cancer remains unclear. Our protein and RNA level analysis from archived specimens and public databases show that USP10 is overexpressed in pancreatic ductal adenocarcinoma (PDAC) and expression correlates with poor overall patient survival.

KRCC1, a modulator of the DNA damage response.

The lysine-rich coiled-coil 1 (KRCC1) protein is overexpressed in multiple malignancies, including ovarian cancer, and overexpression correlates with poor overall survival. Despite a potential role in cancer progression, the biology of KRCC1 remains elusive. Here, we characterize the biology of KRCC1 and define its role in the DNA damage response and in cell cycle progression.

Physiologically Based Pharmacokinetic Modeling and Tissue Distribution Characteristics of SHetA2 in Tumor-Bearing Mice.

The orally available novel small molecule SHetA2 is the lead sulfur-containing heteroarotinoid that selectively inhibits cancer cells over normal cells, and is currently under clinical development for anticancer treatment and cancer prevention. The objective of this study was to assess and characterize the tissue distribution of SHetA2 in tumor-bearing mice by developing a physiologically based pharmacokinetic (PBPK) model. An orthotopic SKOV3 ovarian cancer xenograft mouse model was used to most accurately mimic the ovarian cancer tumor microenvironment in the peritoneal cavity.

HER2/HER3 regulates lactate secretion and expression of lactate receptor mRNA through the MAP3K4 associated protein GIT1.

One of the major features of cancer is Otto Warburg's observation that many tumors have increased extracellular acidification compared to healthy tissues. Since Warburg's observation, the importance of extracellular acidification in cancer is now considered a hallmark of cancer. Human MAP3K4 functions upstream of the p38 and JNK mitogen activated protein kinases (MAPKs).

Bioanalytical method development and validation of HPLCUV assay for the quantification of SHetA2 in mouse and human plasma: Application to pharmacokinetics study.

Background: SHetA2 is an oral anticancer agent being investigated for cancer treatment and prevention. The aim of this study was to develop and validate a simple, cost-effective, and sensitive HPLC-UV method for the quantification of SHetA2 in biological samples and to apply the method to pharmacokinetic studies of the drug.

Methods: Sample preparation for mouse and human plasmas involved liquid-liquid precipitation and extraction using chilled acetonitrile with 2, 3-Diphenylquinoxaline as an internal standard.

Synthesis and evaluation of second generation Flex-Het scaffolds against the human ovarian cancer A2780 cell line.

Flexible Heteroarotinoids (Flex-Hets) are a class of substituted di-aryl compounds that exhibit potent anti-cancer activity without toxicity. They were derived from the more conformationally restricted, 2-atom linker Hets by substitution of the 2-atom linker with a 3-atom urea or thiourea linker, which conferred more potent inhibitory activity against cancer cell lines. The objectives of this structure activity relationship (SAR) study were to determine if a 4-atom acrylamide linker and various substitutions on the terminal aryl ring altered the anti-cancer activity of these second generation Flex-Het compounds compared to the parent Flex-Het compound, SHetA2, which has a thiourea linker and a nitro substituent.

Measurements of adiposity as clinical biomarkers for first-line bevacizumab-based chemotherapy in epithelial ovarian cancer.

Objective: There is a lack of reliable indicators to predict who will benefit most from anti-angiogenic therapy, such as bevacizumab. Recognizing obesity is associated with increased levels of VEGF, the main target of bevacizumab, we sought to assess if adiposity, measured in terms of BMI, subcutaneous fat area (SFA), and visceral fat area (VFA) was prognostic.

Methods: Reviewed 46 patients with advanced EOC who received primary treatment with bevacizumab-based chemotherapy (N=21) or chemotherapy alone (N=25) for whom complete records, CT prior to the first cycle of chemo, and serum were available.

Insulin exerts direct effects on carcinogenic transformation of human endometrial organotypic cultures.

Epidemiological studies suggest an association between elevated insulin levels and endometrial cancer. We studied the effects of insulin on normal endometrial cell proliferation with cytotoxicity assays. Organotypic cultures were used to determine the effects of insulin on the development of malignant histological features and anchorage independent growth.

HER2/HER3 regulates extracellular acidification and cell migration through MTK1 (MEKK4).

Human MAP3K4 (MTK1) functions upstream of mitogen activated protein kinases (MAPKs). In this study we show MTK1 is required for human epidermal growth factor receptor 2/3 (HER2/HER3)-heregulin beta1 (HRG) induced cell migration in MCF-7 breast cancer cells. We demonstrate that HRG stimulation leads to association of MTK1 with activated HER3 in MCF-7 and T-47D breast cancer cells.

CAP37 activation of PKC promotes human corneal epithelial cell chemotaxis.

Purpose: The objective of this study was to elucidate the signaling pathway through which cationic antimicrobial protein of 37 kDa (CAP37) mediates human corneal epithelial cell (HCEC) chemotaxis.

Methods: Immortalized HCECs were treated with pertussis toxin (10 and 1000 ng/mL), protein kinase C (PKC) inhibitors (calphostin c, 50 nM and Ro-31-8220, 100 nM), phorbol esters (phorbol 12,13-dibutyrate, 200 nM and phorbol 12-myristate 13-acetate, 1 μM) known to deplete PKC isoforms, and siRNAs (400 nM) before a modified Boyden chamber assay was used to determine the effect of these inhibitors and siRNAs on CAP37-directed HCEC migration. PKCδ protein levels, PKCδ-Thr(505) phosphorylation, and PKCδ kinase activity was assessed in CAP37-treated HCECs using immunohistochemistry, Western blotting, and a kinase activity assay, respectively.

Expression of common chromosomal fragile site genes, WWOX/FRA16D and FHIT/FRA3B is downregulated by exposure to environmental carcinogens, UV, and BPDE but not by IR.

Common chromosomal fragile sites are unstable genomic loci susceptible to breakage, rearrangement, and are highly recombinogenic. Frequent alterations at these loci in tumor cells led to the hypothesis that they may contribute to cancer development. The two most common chromosomal fragile sites FRA16D and FRA3B which harbor WWOX and FHIT genes, respectively, are frequently altered in human cancers.