Inhibition of δ-catenin palmitoylation slows the progression of prostate cancer.

Prostate cancer (PCa) is the second leading cause of death in males. It has been reported that δ-catenin expression is upregulated during the late stage of prostate cancer. Palmitoylation promotes protein transport to the cytomembrane and regulates protein localization and function. However, the effect of δ-catenin palmitoylation on the regulation of cancer remains unknown. In this study, we utilized prostate cancer cells overexpressing mutant δ-catenin (J6A cells) to induce a depalmitoylation phenotype and investigate its effect on prostate cancer. Our results indicated that depalmitoylation of δ-catenin not only reduced its membrane expression but also promoted its degradation in the cytoplasm, resulting in a decrease in the effect of EGFR and E-cadherin signaling. Consequently, depalmitoylation of δ-catenin reduced the proliferation and metastasis of prostate cancer cells. Our findings provide novel insights into potential therapeutic strategies for controlling the progression of prostate cancer through palmitoylation-based targeting of δ-catenin.

BV2 Membrane-Coated PEGylated-Liposomes Delivered hFGF21 to Cortical and Hippocampal Microglia for Alzheimer's Disease Therapy.

Microglia-mediated inflammation is involved in the pathogenesis of Alzheimer's disease (AD), whereas human fibroblast growth factor 21 (hFGF21) has demonstrated the ability to regulate microglia activation in Parkinson's disease, indicating a potential therapeutic role in AD. However, challenges such as aggregation, rapid inactivation, and the blood-brain barrier hinder its effectiveness in treating AD. This study develops targeted delivery of hFGF21 to activated microglia using BV2 cell membrane-coated PEGylated liposomes (hFGF21@BCM-LIP), preserving the bioactivity of hFGF21. In vitro, hFGF21@BCM-LIP specifically targets Aß1-42-induced BV2 cells, with uptake hindered by anti-VCAM-1 antibody, indicating the importance of VCAM-1 and integrin α4/ß1 interaction in targeted delivery to BV2 cells. In vivo, following subcutaneous injection near the lymph nodes of the neck, hFGF21@BCM-LIP diffuses into lymph nodes and distributes along the meningeal lymphatic vasculature and brain parenchyma in amyloid-beta (Aß1-42)-induced mice. Furthermore, the administration of hFGF21@BCM-LIP to activated microglia improves cognitive deficits caused by Aß1-42 and reduces levels of tau, p-Tau, and BACE1. It also decreases interleukin-6  (IL-6) and tumor necrosis factor-α (TNF-α) release while increasing interleukin-10 (IL-10) release both in vivo and in vitro. These results indicate that hFGF21@BCM-LIP can be a promising treatment for AD, by effectively crossing the blood-brain barrier and targeting delivery to brain microglia via the neck-meningeal lymphatic vasculature-brain parenchyma pathways.

ATB0,+-targeted nanoparticles initiate autophagy suppression to overcome chemoresistance for enhanced colorectal cancer therapy.

Oxaliplatin (OXA) resistance remains the major obstacle to the successful chemotherapy of colorectal cancer (CRC). As a self-protection mechanism, autophagy may contribute to tumor drug resistance, therefore autophagy suppression could be regarded as a possible treatment option in chemotherapy. Cancer cells, especially drug-resistant tumor cells, increase their demand for specific amino acids by expanding exogenous supply and up-regulating de novo synthesis, to meet the needs for excessive proliferation. Therefore, it is possible to inhibit cancer cell proliferation through pharmacologically blocking the entry of amino acid into cancer cells. SLC6A14 (ATB0,+) is an essential amino acid transporter, that is often abnormally up-regulated in most cancer cells. Herein, in this study, we designed oxaliplatin/berbamine-coloaded, ATB0,+-targeted nanoparticles ((O + B)@Trp-NPs) to therapeutically target SLC6A14 (ATB0,+) and inhibit cancer proliferation. The (O + B)@Trp-NPs utilize the surface-modified tryptophan to achieve SLC6A14-targeted delivery of Berbamine (BBM), a compound that is found in a number of plants used in traditional Chinese medicine, which could suppress autolysosome formation though impairing autophagosome-lysosome fusion. We verified the feasibility of this strategy to overcome the OXA resistance during colorectal cancer treatment. The (O + B)@Trp-NPs significantly inhibited the proliferation and decreased the drug resistance of resistant colorectal cancer cells. In vivo, (O + B)@Trp-NPs greatly suppressed the tumor growth in tumor-bearing mice, which is consistent with the in vitro data. This research offers a unique and promising chemotherapeutic treatment for colorectal cancer.

MicroRNA-122 targets δ-catenin to suppress the tumorigenic potential of prostate cancer cells.

δ-Catenin is expressed abundantly in various human cancers, including prostate, brain, breast, and lung carcinomas, and is recognized as an oncogene that promotes cancer cell growth and tumorigenesis. Although several transcriptional and post-translational pathways for δ-catenin regulation have been identified in cancer cells, the potential effects of microRNA-mediated regulation remain elusive. Here, we used a δ-catenin 3'-UTR luciferase reporter assay to identify regulatory microRNAs. Subsequent bioinformatics analyses and molecular studies revealed that overexpression of miR-122 downregulated δ-catenin expression significantly via targeted binding to a seed sequence in the 3'-UTR region of δ-catenin, and suppressed the invasion, migration, and proliferation of prostate cancer cells in vitro. In a TRAMP-C2 mouse syngeneic prostate tumor model, stable expression of miR-122 decreased both δ-catenin expression and tumor growth. Mechanistically, overexpression of miR-122 inhibited the expression of δ-catenin-mediated downstream factors significantly in prostate cancer cells, including c-myc and cyclin D1. In cells overexpressing miR-122, there was no additive or synergistic effect of siRNA-mediated knockdown of δ-catenin on cell invasiveness, and overexpression of miR-122 alone had a more pronounced suppressive effect on cell invasion than knockdown of δ-catenin alone. These results suggest that miR-122 acts as tumor suppressor in prostate cancer, mainly by downregulating δ-catenin expression, but also by targeting other factors. Indeed, subsequent experiments showed that overexpression of miR-122 reduced the levels of the mRNAs encoding myc, snail, and VEGF in prostate cancer cells. Overall, our findings demonstrate that targeting of δ-catenin by miR-122 represses the motility and tumorigenesis of prostate cancer cells, indicating a tumor suppressive effect of this miRNA in prostate cancer.

Carbidopa suppresses estrogen receptor-positive breast cancer via AhR-mediated proteasomal degradation of ERα.

Estrogen receptor-α (ERα) promotes breast cancer, and ER-positive cancer accounts for ~ 80% of breast cancers. This subtype responds positively to hormone/endocrine therapies involving either inhibition of estrogen synthesis or blockade of estrogen action. Carbidopa, a drug used to potentiate the therapeutic efficacy of L-DOPA in Parkinson's disease, is an agonist for aryl hydrocarbon receptor (AhR). Pharmacotherapy in Parkinson's disease decreases the risk for cancers, including breast cancer. The effects of carbidopa on ER-positive breast cancer were evaluated in cell culture and in mouse xenografts. The assays included cell proliferation, apoptosis, cell migration/invasion, subcellular localization of AhR, proteasomal degradation, and tumor growth in xenografts. Carbidopa decreased proliferation and migration of ER-positive human breast cancer cells in vitro with no significant effect on ER-negative breast cancer cells. Treatment of ER-positive cells with carbidopa promoted nuclear localization of AhR and expression of AhR target genes; it also decreased cellular levels of ERα via proteasomal degradation in an AhR-dependent manner. In vivo, carbidopa suppressed the growth of ER-positive breast cancer cells in mouse xenografts; this was associated with increased apoptosis and decreased cell proliferation. Carbidopa has therapeutic potential for ER-positive breast cancer either as a single agent or in combination with other standard chemotherapies.

δ-Catenin promotes cell migration and invasion via Bcl-2-regulated suppression of autophagy in prostate cancer cells.

As a member of the catenin family, δ-catenin is overexpressed in many cancers, including prostate cancer, and the role of δ-catenin in prostate tumor growth has been reported. However, the involvement of δ-catenin in the migration and invasion of prostate cancer has rarely been studied. In this study, we innovatively proposed that δ-catenin would enhance the migration and invasion ability of prostate cancer cells. It is worth noting that the molecular mechanism underlying the effect involved the downregulation of autophagy. We demonstrated that δ-catenin could suppress autophagy by Bcl-2-regulated disruption of the Beclin1-Vps34 autophagosome complex. Furthermore, the effect of δ-catenin on promoting cell migration and invasion was dependent upon ß-catenin-mediated Bcl-2 transcription. Finally, using rapamycin and bafilomycin, we largely confirmed that the degradation of Snails by autolysosomes may be related to δ-catenin regulated migration and invasion. Overall, our results indicated that δ-catenin promoted cell migration and invasion of prostate cancer cells via Bcl-2-regulated autophagy suppression.

bFGF-mediated phosphorylation of δ-catenin increases its protein stability and the ability to induce the nuclear redistribution of ß-catenin.

Recently, we have shown that δ-catenin strengthened the epidermal growth factor receptor (EGFR)/Erk1/2 signaling pathway through the association between EGFR and δ-catenin. Now, we further analyzed the correlation between basic fibroblast growth factor (bFGF)/fibroblast growth factor receptor 1 (FGFR1) and δ-catenin in prostate cancer and investigated the molecular mechanism underlying the role of bFGF/FGFR1 modulation in CWR22Rv-1 (Rv-1) cells. Here, we demonstrated that bFGF phosphorylated the tyrosine residues of δ-catenin in Rv-1 cells and further proved that the bFGF mediated FGFR1/δ-catenin tyrosine phosphorylation was time dependent. Furthermore, we demonstrated that bFGF stabilized the expression of δ-catenin through weakening its association with GSK3ß and enhancing its stability to induce ß-catenin into the nuclear by strengthening the processing of E-cadherin. In a word, these results indicated that bFGF/FGFR1 signaling pathway could enhance the tumor progression of prostate cancer via δ-catenin.

A heptamethine cyanine dye serves as a potential marker for myeloid-derived suppressor cells.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells with inhibitory effects on T cell-mediated immune response. MDSCs accumulate under many pathological conditions, including cancers, to avoid anticancer immunity. Unlike mouse MDSCs, common specific surface markers for human MDSCs are not clearly defined, mainly due to the complexity of MDSC subsets. In this study, we investigate specific responses of the infrared dye MHI-148 to MDSCs. Mice bearing 4T1 breast cancer cells were established, and splenocytes were isolated. Flow cytometric analyses demonstrated that MHI-148 was reactive to over 80% of MDSC-specific cells manifesting CD11b+/Gr-1+ acquired from both tumor-bearing mice and naive mice. Cells sorted positive for either CD11b/Gr-1 or MHI-148 were also identical to their counterparts (99.7% and 97.7%, respectively). MHI-148, however, was not reactive to lymphocyte or monocyte populations. To determine whether MHI-148-reactive cells exert inhibitory effects on T cell proliferation, an EdU-based T cell assay was performed. MHI-148 reactive cells significantly reduced T cell proliferation with increased arginase activity and nitrite production. In an attempt to test MHI-148 as a marker for human MDSCs, MHI-148 was specifically reactive to CD11b+/CD33+/CD14- granulocytic MDSCs acquired from selected cancer patients. This study demonstrates that the near-infrared dye MHI-148 specifically reacts to mouse splenocytes with known MDSC-specific markers that have T cell suppressive functions. The dye also selectively binds to a subpopulation of immature myeloid cells acquired from cancer patients. While it is not clear how MHI-148 specifically stains MDSCs, this dye can be a novel tool to detect MDSCs and to predict the prognosis of human cancer patients.

δ-Catenin Participates in EGF/AKT/p21Waf Signaling and Induces Prostate Cancer Cell Proliferation and Invasion.

Prostate cancer (PCa) is the second most leading cause of death in males. Our previous studies have demonstrated that δ-catenin plays an important role in prostate cancer progression. However, the molecular mechanism underlying the regulation of δ-catenin has not been fully explored yet. In the present study, we found that δ-catenin could induce phosphorylation of p21Waf and stabilize p21 in the cytoplasm, thus blocking its nuclear accumulation for the first time. We also found that δ-catenin could regulate the interaction between AKT and p21, leading to phosphorylation of p21 at Thr-145 residue. Finally, EGF was found to be a key factor upstream of AKT/δ-catenin/p21 for promoting proliferation and metastasis in prostate cancer. Our findings provide new insights into molecular controls of EGF and the development of potential therapeutics targeting δ-catenin to control prostate cancer progression.

bFGF alleviates diabetes-associated endothelial impairment by downregulating inflammation via S-nitrosylation pathway.

Protein S-nitrosylation is a reversible protein modification implicated in both physiological and pathophysiological regulation of protein function. However, the relationship between dysregulated S-nitrosylation homeostasis and diabetic vascular complications remains incompletely understood. Here, we demonstrate that basic fibroblast growth factor (bFGF) is a key regulatory link between S-nitrosylation homeostasis and inflammation, and alleviated endothelial dysfunction and angiogenic defects in diabetes. Subjecting human umbilical vein endothelial cells (HUVECs) to hyperglycemia and hyperlipidemia significantly decreased endogenous S-nitrosylated proteins, including S-nitrosylation of inhibitor kappa B kinase ß (IKKßC179) and transcription factor p65 (p65C38), which was alleviated by bFGF co-treatment. Pretreatment with carboxy-PTIO (c-PTIO), a nitric oxide scavenger, abolished bFGF-mediated S-nitrosylation increase and endothelial protection. Meanwhile, nitrosylation-resistant IKKßC179S and p65C38S mutants exacerbated endothelial dysfunction in db/db mice, and in cultured HUVECs subjected to hyperglycemia and hyperlipidemia. Mechanistically, bFGF-mediated increase of S-nitrosylated IKKß and p65 was attributed to synergistic effects of increased endothelial nitric oxide synthase (eNOS) and thioredoxin (Trx) activity. Taken together, the endothelial protective effect of bFGF under hyperglycemia and hyperlipidemia can be partially attributed to its role in suppressing inflammation via the S-nitrosylation pathway.

Anti-Cancer Effects of Glaucarubinone in the Hepatocellular Carcinoma Cell Line Huh7 via Regulation of the Epithelial-To-Mesenchymal Transition-Associated Transcription Factor Twist1.

Hepatocellular carcinoma (HCC), the most common type of liver cancer, is a leading cause of cancer-related deaths. As HCC has a high mortality rate and its incidence is increasing worldwide, understanding and treating HCC are crucial for resolving major public health concerns. In the present study, wound healing screening assays were performed using natural product libraries to identify natural chemicals that can inhibit cancer cell migration. Glaucarubinone (GCB) showed a high potential for inhibiting cell migration. The anti-cancer effects of GCB were evaluated using the HCC cell line, Huh7. GCB showed anti-cancer effects, as verified by wound healing, cell migration, invasion, colony formation, and three-dimensional spheroid invasion assays. In addition, cells treated with GCB showed suppressed matrix metalloproteinase activities. Immunoblotting analyses of intracellular signaling pathways revealed that GCB regulated the levels of Twist1, a crucial transcription factor associated with epithelial-to-mesenchymal transition, and mitogen-activated protein kinase. The invasive ability of cancer cells was found to be decreased by the regulation of Twist1 protein levels. Furthermore, GCB downregulated phosphorylation of extracellular signal-regulated kinase. These results indicate that GCB exhibits anti-metastatic properties in Huh7 cells, suggesting that it could be used to treat HCC.

Development of a Multiplex Bead-Based Method for the Microquantitation of δ-Catenin.

δ-Catenin is overexpressed in human cancers, including prostate, breast, lung, and ovarian cancers. Therefore, detection of δ-catenin level in patient specimens can be used as a diagnostic marker for the cancer screening. In laboratories, δ-catenin levels have been analyzed by western blot, which requires multiple procedures and is incapable of multiplex analysis of a target protein from a single reaction. In this study, we aimed to develop δ-catenin antibody-conjugated magnetic beads that can be used for quantitation of δ-catenin by bead-based multiplex assay. δ-catenin level from HEK293T and CWR22Rv-1 cell lysates was quantified to determine whether the antibody-conjugatedmagnetic bead can be used for the detection of trace amounts of δ-catenin. Our results indicate that analysis with 1 µg of CWR22Rv-1 and HEK293T cell lysates showed 918.67±103.8 and 874.33±37.21 MFI values, respectively. In conclusion, the results suggest that the procedure for detection of δ-catenin level through the antibody-conjugated magnetic beads provides a sensitive and costeffective solution for screening from patient specimens.

p300/CBP-associated factor promotes autophagic degradation of δ-catenin through acetylation and decreases prostate cancer tumorigenicity.

δ-Catenin shares common binding partners with ß-catenin. As acetylation and deacetylation regulate ß-catenin stability, we searched for histone acetyltransferases (HATs) or histone deacetylases (HDACs) affecting δ-catenin acetylation status and protein levels. We showed that p300/CBP-associated factor (PCAF) directly bound to and acetylated δ-catenin, whereas several class I and class II HDACs reversed this effect. Unlike ß-catenin, δ-catenin was downregulated by PCAF-mediated acetylation and upregulated by HDAC-mediated deacetylation. The HDAC inhibitor trichostatin A attenuated HDAC1-mediated δ-catenin upregulation, whereas HAT or autophagy inhibitors, but not proteasome inhibitors, abolished PCAF-mediated δ-catenin downregulation. The results suggested that PCAF-mediated δ-catenin acetylation promotes its autophagic degradation in an Atg5/LC3-dependent manner. Deletions or point mutations identified several lysine residues in different δ-catenin domains involved in PCAF-mediated δ-catenin downregulation. PCAF overexpression in prostate cancer cells markedly reduced δ-catenin levels and suppressed cell growth and motility. PCAF-mediated δ-catenin downregulation inhibited E-cadherin processing and decreased the nuclear distribution of ß-catenin, resulting in the suppression of ß-catenin/LEF-1-mediated downstream effectors. These data demonstrate that PCAF downregulates δ-catenin by promoting its autophagic degradation and suppresses δ-catenin-mediated oncogenic signals.

Effects of δ-Catenin on APP by Its Interaction with Presenilin-1.

Alzheimer's disease (AD) is the most frequent age-related human neurological disorder. The characteristics of AD include senile plaques, neurofibrillary tangles, and loss of synapses and neurons in the brain. ß-Amyloid (Aß) peptide is the predominant proteinaceous component of senile plaques. The amyloid hypothesis states that Aß initiates the cascade of events that result in AD. Amyloid precursor protein (APP) processing plays an important role in Aß production, which initiates synaptic and neuronal damage. δ-Catenin is known to be bound to presenilin-1 (PS-1), which is the main component of the γ-secretase complex that regulates APP cleavage. Because PS-1 interacts with both APP and δ-catenin, it is worth studying their interactive mechanism and/or effects on each other. Our immunoprecipitation data showed that there was no physical association between δ-catenin and APP. However, we observed that δ-catenin could reduce the binding between PS-1 and APP, thus decreasing the PS-1 mediated APP processing activity. Furthermore, δ-catenin reduced PS-1-mediated stabilization of APP. The results suggest that δ-catenin can influence the APP processing and its level by interacting with PS-1, which may eventually play a protective role in the degeneration of an Alzheimer's disease patient.

δ-Catenin Increases the Stability of EGFR by Decreasing c-Cbl Interaction and Enhances EGFR/Erk1/2 Signaling in Prostate Cancer.

δ-Catenin, a member of the p120-catenin subfamily of armadillo proteins, reportedly increases during the late stage of prostate cancer. Our previous study demonstrates that δ-catenin increases the stability of EGFR in prostate cancer cell lines. However, the molecular mechanism behind δ-catenin-mediated enhanced stability of EGFR was not explored. In this study, we hypothesized that δ-catenin enhances the protein stability of EGFR by inhibiting its lysosomal degradation that is mediated by c-casitas b-lineage lymphoma (c-Cbl), a RING domain E3 ligase. c-Cbl monoubiquitinates EGFR and thus facilitates its internalization, followed by lysosomal degradation. We observed that δ-catenin plays a key role in EGFR stability and downstream signaling. δ-Catenin competes with c-Cbl for EGFR binding, which results in a reduction of binding between c-Cbl and EGFR and thus decreases the ubiquitination of EGFR. This in turn increases the expression of membrane bound EGFR and enhances EGFR/Erk1/2 signaling. Our findings add a new perspective on the role of δ-catenin in enhancing EGFR/Erk1/2 signaling-mediated prostate cancer.

Dual-specificity phosphatase 5 acts as an anti-inflammatory regulator by inhibiting the ERK and NF-κB signaling pathways.

Although dual-specificity phosphatase 5 (DUSP5), which inactivates extracellular signal-regulated kinase (ERK), suppresses tumors in several types of cancer, its functional roles remain largely unknown. Here, we show that DUSP5 is induced during lipopolysaccharide (LPS)-mediated inflammation and inhibits nuclear factor-κB (NF-κB) activity. DUSP5 mRNA and protein expression increased transiently in LPS-stimulated RAW 264.7 cells and then returned to basal levels. DUSP5 overexpression in RAW 264.7 cells suppressed the production of pro-inflammatory tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), whereas knockdown of DUSP5 increased their expression. Investigation of two major inflammatory signaling pathways, mitogen-activated protein kinase (MAPK) and NF-κB, using activator protein-1 (AP-1) and NF-κB reporter plasmids, respectively, showed that NF-κB transcription activity was downregulated by DUSP5 in a phosphatase activity-independent manner whereas AP-1 activity was inhibited by DUSP5 phosphatase activity towards ERK,. Further investigation showed that DUSP5 directly interacts with transforming growth factor beta-activated kinase 1 (TAK1) and inhibitor of κB (IκB) kinases (IKKs) but not with IκBα. DUSP5 binding to IKKs interfered with the association of TAK1 with IKKs, suggesting that DUSP5 might act as a competitive inhibitor of TAK1-IKKs association. Therefore, we propose that DUSP5 negatively regulates ERK and NF-κB in a phosphatase activity-dependent and -independent manner, respectively.

Bromopropane Compounds Increase the Stemness of Colorectal Cancer Cells.

Bromopropane (BP) compounds, including 1-bromopropane, 2-bromopropane, and 1,2-dibromopropane, are used in industry for various purposes, and their deleterious effects on human health are becoming known. In this study, we examined the effects of BP compounds on the stemness of colorectal cancer cells. At low, non-cytotoxic concentrations, BP compounds significantly increased spheroid formation in CSC221, DLD1, Caco2, and HT29 cells. In addition, the levels of cancer stem cell markers, such as aldehyde dehydrogenase-1, cluster of differentiation 133 (CD133), CD44, Lgr5, Musashi-1, Ephrin receptor, and Bmi-1 increased after exposure to BP compounds. BP compounds increased the transcriptional activity of the TOPflash and glioma-associated oncogene homolog zinc finger protein (Gli) promoters in reporter assays and increased the expression of Gli-1, Gli-2, Smoothened (SMO), and ß-catenin by RT-PCR. These results demonstrate for the first time that BP compounds have the potential to promote cancer stemness.

Hakai, an E3-ligase for E-cadherin, stabilizes δ-catenin through Src kinase.

Hakai ubiquitinates and induces endocytosis of the E-cadherin complex; thus, modulating cell adhesion and regulating development of the epithelial-mesenchymal transition of metastasis. Our previous published data show that δ-catenin promotes E-cadherin processing and thereby activates ß-catenin-mediated oncogenic signals. Although several published data show the interactions between δ-catenin and E-cadherin and between Hakai and E-cadherin separately, we found no published report on the relationship between δ-catenin and Hakai. In this report, we show Hakai stabilizes δ-catenin regardless of its E3 ligase activity. We show that Hakai and Src increase the stability of δ-catenin synergistically. Hakai stabilizes Src and Src, which in turn, inhibits binding between glycogen synthase kinase-3ß and δ-catenin, resulting in less proteosomal degradation of δ-catenin. These results suggest that stabilization of δ-catenin by Hakai is dependent on Src.

Investigation of the molecular mechanism of δ-catenin ubiquitination: Implication of ß-TrCP-1 as a potential E3 ligase.

Ubiquitination, a post-translational modification, involves the covalent attachment of ubiquitin to the target protein. The ubiquitin-proteasome pathway and the endosome-lysosome pathway control the degradation of the majority of eukaryotic proteins. Our previous study illustrated that δ-catenin ubiquitination occurs in a glycogen synthase kinase-3 (GSK-3) phosphorylation-dependent manner. However, the molecular mechanism of δ-catenin ubiquitination is still unknown. Here, we show that the lysine residues required for ubiquitination are located mainly in the C-terminal portion of δ-catenin. In addition, we provide evidence that ß-TrCP-1 interacts with δ-catenin and functions as an E3 ligase, mediating δ-catenin ubiquitin-proteasome degradation. Furthermore, we prove that both the ubiquitin-proteasome pathway and the lysosome degradation pathway are involved in δ-catenin degradation. Our novel findings on the mechanism of δ-catenin ubiquitination will add a new perspective to δ-catenin degradation and the effects of δ-catenin on E-cadherin involved in epithelial cell-cell adhesion, which is implicated in prostate cancer progression.

Efficacy of CD46-targeting chimeric Ad5/35 adenoviral gene therapy for colorectal cancers.

CD46 is a complement inhibitor membrane cofactor which also acts as a receptor for various microbes, including species B adenoviruses (Ads). While most Ad gene therapy vectors are derived from species C and infect cells through coxsackie-adenovirus receptor (CAR), CAR expression is downregulated in many cancer cells, resulting inefficient Ad-based therapeutics. Despite a limited knowledge on the expression status of many cancer cells, an increasing number of cancer gene therapy studies include fiber-modified Ad vectors redirected to the more ubiquitously expressed CD46. Since our finding from tumor microarray indicate that CD46 was overexpressed in cancers of the prostate and colon, fiber chimeric Ad5/35 vectors that have infection tropism for CD46 were employed to demonstrate its efficacy in colorectal cancers (CRC). CD46-overexpressed cells showed a significantly higher response to Ad5/35-GFP and to Ad5/35-tk/GCV. While CRC cells express variable levels of CD46, CD46 expression was positively correlated with Ad5/35-mediated GFP fluorescence and accordingly its cell killing. Injection of Ad5/35-tk/GCV caused much greater tumor-suppression in mice bearing CD46-overexpressed cancer xenograft compared to mock group. Analysis of CRC samples revealed that patients with positive CD46 expression had a higher survival rate (p=0.031), carried tumors that were well-differentiated, but less invasive and metastatic, and with a low T stage (all p<0.05). Taken together, our study demonstrated that species B-based adenoviral gene therapy is a suitable approach for generally CD46-overexpressed CRC but would require careful consideration preceding CD46 analysis and categorizing CRC patients.