A search for differentially expressed genes in a pair of nonmetastatic (PC-3) versus metastatic variant (PC-3M) human prostate carcinoma cell lines led to identification of the human heat shock factor (HSF1) as an overexpressed gene product in PC-3M cells. Analysis of primary prostate cancer specimens indicated that HSF1 is generally up-regulated in most of the malignant prostate epithelial cells relative to the normal prostate cells. Among the known effectors of HSF1 action, constitutive levels of HSP70 and HSP90 are not significantly altered by the naturally elevated expression of HSF1 as in PC-3M cells or by transduced overexpression of HSF1 in PC-3 cells. The basal levels of HSP27 in both cases are, however, consistently increased by two- to threefold. With respect to response to heat shock, high basal concentration of HSP90 is not further enhanced in these cells, and HSP70 is up-regulated irrespective of HSF1 level. Heat shock, however, causes an increase in HSP27 when HSF1 is up-regulated, except when the expression of HSF1 is already too high. These results document for the first time that HSF1 is overexpressed in human prostate cancer cells, at least one consequence of which in the prostate cancer cell lines tested is stimulation of both basal and stress-induced expression of HSP27, an important factor in cell growth, differentiation, or apoptosis.
The gamma subfamily of herpesviruses, including EpsteinBarr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) or human herpesvirus 8 (HHV-8), are associated with tumors and lymphoproliferative disorders (29,43). Murine gammaherpesvirus 68 (MHV-68) is phylogenetically related to EBV and KSHV and provides major research advantages by forming plaques on cell monolayers and establishing productive lytic and latent infections in mice (10,(64)(65)(66). Unlike EBV and KSHV, MHV-68 readily establishes productive infections in many cell culture systems and thus facilitates the examination of gammaherpesvirus replication and de novo infection (66,75,76). This provides an opportunity to examine cellular responses to de novo infection and their role in regulating gammaherpesvirus activity.Prostaglandins (PGs) are potent immunoregulatory lipid mediators generated by arachidonic acid metabolism via two cellular cyclooxygenases, constitutive COX-1 and inducible 22,26,61). PGs are formed by most cell types and exert a variety of actions in various tissues and cells via PG receptors (2,16,19,33,47). PGE 2 is an important proinflammatory prostanoid that mediates many symptoms of inflammation (41,53,56,70). Production of PGE 2 is catalyzed by COX-2, which is induced in response to factors such as bacterial lipopolysaccharides, mitogens, and cytokines (17,31,57,61). However, it is unknown what role the COX-2-PGE 2 pathway might play in responding to gammaherpesvirus de novo infection.Many viruses have been linked to the modulation of COX-2 expression and PG production (9,11,25,44,46,52,60,63,(77)(78)(79). COX-2 is responsible for the exaggerated biosynthesis of PGs under acute inflammatory conditions and in a diverse group of tumors (14,23,32,67). The COX-1 and COX-2 isozymes are the pharmacologic targets of nonsteroidal antiinflammatory drugs (NSAIDs) (26,50,61,71), and NSAIDs that block COX activity and PG production have been recognized as potentially effective antiviral therapeutics (4, 6-8, 51, 62, 73, 79). However, the effect of COX inhibitors on de novo infection of a gammaherpesvirus has not been previously examined. MHV-68 has been used as a model to study the efficacy of other antiviral compounds (3, 48, 49, 68), and we used this system to address the effects of COX-2 inhibition on gammaherpesvirus replication and infection.To enhance our understanding of virus-host cell interactions involved in the replication and pathogenesis of gammaherpesviruses, we examined MHV-68 de novo infection of NIH 3T3 and BHK-21 cells as a model for analyzing the role of PG production and COX-2 activity. We compared the effects of MHV-68 and UV-irradiated MHV-68 infection on COX-2 protein expression and COX-2 promoter activation. COX inhibitors {NS-398 [N-(2-cyclohexyloxy-4-nitrophenyl)-methanesulfonamide] and indomethacin} were tested for their ability to suppress MHV-68 protein expression during de novo infection. Inhibition of protein expression and virion production by NS-398 was relieved in the presence of exogenous PGE 2 ,...
Based on the finding that gene expression for the actin-bundling protein L-plastin is inducible by androgen and that L-plastin is overexpressed in malignant epithelium of the prostate, we examined the functional consequences of L-plastin down-regulation in prostate carcinoma cell lines by both transfection and retroviral infection. We constructed retroviral vectors to express two different regions of the L-plastin gene, a 1713-bp 3'-coding portion and a 163-bp 5'-untranslated region, both in antisense orientation. Introduction of either constructs into prostate carcinoma cell lines, PC-3 and its isogenic but metastatic variant PC-3M cells, reduced the growth rates of both cell lines. In vitro invasion and motility of PC-3 and PC-3M cells were drastically suppressed (approximately 10-fold) by the expression of the antisense constructs. Evidence was obtained to indicate that L-plastin protein levels were indeed decreased by the antisense expression. The antisense construct for the 5'-untranslated region with the most unique sequence for the L-plastin gene was more effective in down-regulation efficiency compared with the larger antisense construct in the coding region, which maintains homology to other members of the plastin gene family. Cells infected with the 163-bp antisense virus, which were also tested in a nude mouse diaphragm invasion model, showed suppression of in vivo invasion of both PC-3 and PC-3M cells. These results suggested that overexpression of L-plastin might be functionally involved in prostate cancer invasion and metastasis, and raised the possibility that L-plastin gene-specific antisense delivery could potentially be a useful approach to interfere with prostate cancer progression in vivo.
TRAIL can activate cell surface death receptors, resulting in potent tumor cell death via induction of the extrinsic apoptosis pathway. Eftozanermin alfa (ABBV-621) is a second generation TRAIL receptor agonist engineered as an IgG1-Fc mutant backbone linked to two sets of trimeric native single-chain TRAIL receptor binding domain monomers. This hexavalent agonistic fusion protein binds to the death-inducing DR4 and DR5 receptors with nanomolar affinity to drive on-target biological activity with enhanced caspase-8 aggregation and death-inducing signaling complex formation independent of FcγR-mediated cross-linking, and without clinical signs or pathologic evidence of toxicity in nonrodent species. ABBV-621 induced cell death in approximately 36% (45/126) of solid cancer cell lines in vitro at subnanomolar concentrations. An in vivo patient-derived xenograft (PDX) screen of ABBV-621 activity across 15 different tumor indications resulted in an overall response (OR) of 29% (47/162). Although DR4 (TNFSFR10A) and/or DR5 (TNFSFR10B) expression levels did not predict the level of response to ABBV-621 activity in vivo, KRAS mutations were associated with elevated TNFSFR10A and TNFSFR10B and were enriched in ABBV-621–responsive colorectal carcinoma PDX models. To build upon the OR of ABBV-621 monotherapy in colorectal cancer (45%; 10/22) and pancreatic cancer (35%; 7/20), we subsequently demonstrated that inherent resistance to ABBV-621 treatment could be overcome in combination with chemotherapeutics or with selective inhibitors of BCL-XL. In summary, these data provide a preclinical rationale for the ongoing phase 1 clinical trial (NCT03082209) evaluating the activity of ABBV-621 in patients with cancer. Significance: This study describes the activity of a hexavalent TRAIL-receptor agonistic fusion protein in preclinical models of solid tumors that mechanistically distinguishes this molecular entity from other TRAIL-based therapeutics.
Discoidin domain receptor 1 (DDR1) is a member of the receptor tyrosine kinase family. The receptor is activated upon binding to its ligand, collagen, and plays a crucial role in many fundamental processes such as cell differentiation, adhesion, migration and invasion. Although DDR1 is expressed in many normal tissues, upregulated expression of DDR1 in a variety of human cancers such as lung, colon and brain cancers is known to be associated with poor prognosis. Using shRNA silencing, we assessed the oncogenic potential of DDR1. DDR1 knockdown impaired tumor cell proliferation and migration in vitro and tumor growth in vivo. Microarray analysis of tumor cells demonstrated upregulation of TGFBI expression upon DDR1 knockdown, which was subsequently confirmed at the protein level. TGFBI is a TGFβ-induced extracellular matrix protein secreted by the tumor cells and is known to act either as a tumor promoter or tumor suppressor, depending on the tumor environment. Here, we show that exogenous addition of recombinant TGFBI to BXPC3 tumor cells inhibited clonogenic growth and migration, thus recapitulating the phenotypic effect observed from DDR1 silencing. BXPC3 tumor xenografts demonstrated reduced growth with DDR1 knockdown, and the same xenograft tumors exhibited an increase in TGFBI expression level. Together, these data suggest that DDR1 expression level influences tumor growth in part via modulation of TGFBI expression. The reciprocal expression of DDR1 and TGFBI may help to elucidate the contribution of DDR1 in tumorigenesis and TGFBI may also be used as a biomarker for the therapeutic development of DDR1 specific inhibitors.
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