Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Utilizing melanoma and sarcoma tumor models syngeneic to C57BL/6 mice, we previously reported the antitumor effects of intratumoral (i.t.) administration of dendritic cells (DC) combined with localized radiotherapy (RT). However, the mechanisms underlying the augmented therapeutic effects have yet to be fully defined. Using the BALB/c host, we explored in this study the capacity of RT to augment the therapeutic efficacy of DC in the syngeneic renal cell cancer, Renca. I.t. DC administration combined with RT inhibited tumor growth in a synergistic manner. This extends our previous findings using a different host strain and two histologically distinct tumor models. More importantly, we provide evidence in this report that RT induced significant apoptosis and necrosis in Renca tumor cells, which involved down-regulated expression of Bcl-2 and a concurrent up-regulated expression of Bax. We also found significantly elevated expression of TNFalpha in RT plus DC-treated Renca tumors. Furthermore, splenocytes isolated from DC plus RT-treated mice elaborated higher levels of IL-2, IL-4, IFNgamma and IgG, IgM in response to tumor cells compared with splenocytes from monotherapy-treated hosts. These data support the conclusion that radiotherapy enhanced DC vaccination by inducing tumor cell apoptosis in BABL/c host, and the significantly augmented therapeutic efficacy by RT+DC treatment was associated with an increased local production of TNFalpha as well as an amplified systemic antitumor responses conferred by the combined therapy. I.t. DC administration in concert with localized RT may represent a promising novel regimen for human cancer therapy.
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PMID:Radiation-induced apoptosis along with local and systemic cytokine elaboration is associated with DC plus radiotherapy-mediated renal cell tumor regression. 1744 28

Renal cell carcinoma (RCC) is resistant to chemotherapy, and this resistance is mirrored by a high apoptosis resistance of many RCC lines in vitro. Here, we report the loss of the pro-apoptotic BH3-only protein Bim in a large part of clinical RCC cases and provide evidence for a functional relevance of this loss. Immunohistochemistry of clear cell renal cell carcinoma cases and corresponding normal kidney showed strong Bim reactivity in renal tubules of all cases but loss of Bim in 35 of 45 RCC samples. Out of nine RCC cell lines investigated, six showed strongly diminished or undetectable levels of Bim protein by western blotting. Four RCC lines of varying apoptosis sensitivity were analysed further. Bcl-2, Bcl-x(L), Mcl-1, Bax and Bak expression did not correlate with apoptosis sensitivity. All cell lines underwent apoptosis upon forced expression of Bax and Bim, suggesting an upstream difference. In all four lines, adriamycin induced p53 but not its targets Puma or Noxa. However, apoptosis sensitivity correlated with levels of Bim protein. Bim siRNA reduced apoptosis sensitivity in a susceptible cell line. Furthermore, inhibition of histone deacetylation restored Bim expression in cell lines. These data suggest that Bim has a function as a tumor suppressor in RCC.
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PMID:Frequent loss of expression of the pro-apoptotic protein Bim in renal cell carcinoma: evidence for contribution to apoptosis resistance. 1748 61

Dysfunction in apoptosis has been suggested to play an important role in the development of a distant metastasis. The Bcl-2 gene plays a key role in the response to chemotherapeutic agents, and its upregulation protects the cells from apoptosis by inactivating the Bax proteins through heterodimerization of Bcl-2/Bax. However, there is no direct evidence showing that the upregulation of Bcl-2 increases the antiapoptotic effects against chemotherapeutic agents and is associated with the production of a distant metastasis. In this study, the role of Bcl-2 in the production of distant metastasis was investigated by examining the activity of caspase-3 and the expression of matrix metalloproteinases (MMPs) after transfecting the Bcl-2 gene into human renal cell carcinoma cells (SN12C). In addition, the production of a distant metastasis was examined in an orthotopic animal model. In vitro, the SN12C/smb2 cells were more resistant to doxorubicin (DXR) than the untreated parental cells. The IC50 of the SN12C/smb2 was 50% higher than that of the parental cells. In addition, the caspase-3 activity of the SN12C/smb2 cells was lower than that of the parental cells after the DXR treatment. On the other hand, there was no difference in the expression of MMP-2 and MMP-9 between the SN12C and SN12C/smb2 cell lines. However, the SN12C/smb2 cells had a higher metastatic potential than the parental cells in the orthotopic animal model. Unlike the results from the in vitro analysis, the expression of MMP-2 and MMP-9 in the kidney tumors produced by the SN12C/smb2 cells was higher than in the kidney tumors produced by the SN12C/vector. These results show that the upregulation of Bcl-2 in human renal cell carcinoma cells induces drug resistance to DXR. Moreover, Bcl-2 induced the expression of MMP in tumors grown in the orthotopic sites even though no appreciable effects were observed in the in vitro condition. When the in vitro and in vivo data were combined, it appears that the Bcl-2 gene initially affects the response to DXR. The cells that survive the DXR treatment then have a chance to become metastatic by increasing the levels of MMP in an orthotopic environment.
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PMID:Microenvironment effects on promoting upregulation of matrix metalloproteinases in Bcl-2-overexpressing renal cell carcinoma as a response to doxorubicin treatment inducing the production of metastasis. 1754 5

Metastases in renal carcinoma are diagnosed at initial diagnosis in 25% examinees. Traditional renal carcinoma has higher metastatic potential, is associated with worse survival of the patients compared to papillary cancer. We studied cytological characteristics of renal carcinoma metastases to the pleura in comparison with histological studies of the primary lesion using immunohistochemical findings. We examined cytologically pleural liquid in renal carcinoma metastases to the pleura in 6 patients (2.3% of carcinomatous pleuricies). High efficacy was shown by a cytocentrifuge CYTOSPIN-4. In 3 cases initial cancer was renal cell carcinoma, pleural exudation developed 2 years later, clear cell carcinoma appeared 6 years later and papillary cancer--10 years later. In the other 3 cases malignant cells were detected in new-onset cases. Renal carcinoma was diagnosed in one case. Cytological preparations were studied with identification of cytological signs typical for classic clear cell, granulocell and papillary renal cancer. Immunohistochemical examination of primary tumor lesion in the kidney discovered high proliferative activity of tumor cells by Ki-67 index to 5.28%. The tumors had solitary Bcl-2 positive cells. Expression of mutant p-53 took place in 0.93%. Her-2/neu hyperexpression was not found in the tumors of the above patients. Such immunohistochemical parameters point to poor prognosis. This is confirmed by renal carcinoma metastases to the pleura.
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PMID:[Pleural metastases of renal carcinoma]. 1757 98

Anaemia which develops as a consequence of malignancies is often treated using recombinant human erythropoietin (rhEpo). Epo is now known as an anti-apoptotic factor for a wide range of cell types that express Epo receptors (EpoRs) and its co-use with cancer therapies can act detrimentally to diminish therapy-induced apoptosis. This had not been analyzed for renal cell carcinomas (RCCs). We examined the influence of rhEPO on the ability of cisplatin to induce apoptosis in RCCs. Two RCC cell lines (SN12K1 and ACHN) were compared with a non-RCC renal epithelial cell line (HK2). Cells were treated with 50 microM cisplatin with and without 200 IU/mL rhEpo and were compared for apoptosis, mitosis and protein expression of EpoR, nuclear factor-kappaB (NFkappaB), protein kinase C (PKC), Bcl-2, Bax and cyclin-D1. Experiments were repeated with PKC promotion (PMA, 20 nM) or inhibition (H7, 10 microM). rhEpo reduced cisplatin-induced apoptosis in RCCs (p < 0.01), compared with HK-2s. EpoR expression was increased only in SN12K1 with rhEpo, with and without cisplatin. NFkappaB, Bax and Bcl-2 expression was unchanged. PKC protein expression was significantly reduced in cisplatin-treated RCCs with rhEpo, correlating with reduced apoptosis. When the PKC pathway was inhibited in these cells, levels o apoptosis returned to normal for cisplatin treatment, indicating activation of the PKC pathway by rhEpo. PMA promotion increased mitosis only in the RCCs, with and without rhEpo (p < 0.05). In summary, rhEPO reduced cisplatin-induced apoptosis of RCCs and promoted their mitosis via PKC-dependent pathways. This information indicates caution for use of rhEpo in RCC patients for anemias.
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PMID:Erythropoietin reduces cisplatin-induced apoptosis in renal carcinoma cells via a PKC dependent pathway. 1807 99

Renal cell carcinoma (RCC) is known to be resistant to chemo- and radiotherapy due to a high apoptotic threshold. Smac and XIAP (X-linked inhibitor of apoptosis protein) proteins were detected in all RCC cell lines and tissue samples examined. We modulated the function of XIAP, either through its constitutional downregulation with an shRNA vector or by applying a Smac-mimicking peptide. Among RCC cell lines, Caki1 expresses the highest levels of XIAP. We transfected Caki1 with XIAP-targeting shRNA vector and generated stable clones. XIAP was knocked down by RNA interference in clone no. 14 by 81.6% and in clone no. 19 by 85.3%. Compared to the parental and mock-transfected cells, neither clone was more sensitive to conventional chemotherapeutic agents, but both clones were more susceptible to Fas stimulation (P<0.0001) and to pharmacological Bcl-2 inhibition (P<0.0001), as well as to a combination of the two (P<0.0001). Mature Smac binds to XIAP via the N-terminal residues, disrupting its interaction with caspases and promoting their activity. We determined that exposure of Caki1 cells to Smac-N7 peptide (AVPIAQK) resulted in a slight but significant decrease in viability (P=0.0031) and potentiated cisplatin's effect (P=0.0027). In contrast with point targeting of XIAP by shRNA, Smac-N7 peptide is active against several IAP (inhibitor of apoptosis protein) family members, which can explain its role in sensitising cells to cisplatin. Our results suggest that multiple targeting of both Bcl-2 and XIAP or, alternatively, of several IAP family members by the Smac-N7 peptide is a potent way to overcome resistance of RCC to apoptosis-triggering treatment modalities, and might be a new tool for molecular targeted therapy.
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PMID:Double inhibition of XIAP and Bcl-2 axis is beneficial for retrieving sensitivity of renal cell cancer to apoptosis. 1828 11

ABT-263 is a potent, orally bioavailable inhibitor of the antiapoptotic Bcl-2 family members Bcl-2, Bcl-x(L), and Bcl-w, which is currently in phase I clinical trials. Previous work has shown that this compound has low nanomolar cell-killing activity in a variety of lymphoma and leukemia cell lines, many of which overexpress Bcl-2 through a variety of mechanisms. Rapamycin is a macrolide antibiotic that inhibits the mammalian target of rapamycin complex, leading to cell cycle arrest and inhibition of protein translation. Rapamycin (and its analogues) has shown activity in a variety of tumor cell lines primarily through induction of cell cycle arrest. Activity has also been shown clinically in mantle cell lymphoma and advanced renal cell carcinoma. Here, we show that treatment of the follicular lymphoma lines DoHH-2 and SuDHL-4 with 100 nmol/L rapamycin induces substantial G(0)-G(1) arrest. Addition of as little as 39 nmol/L ABT-263 to the rapamycin regimen induced a 3-fold increase in sub-G(0) cells. Combination of these agents also led to a significant increase in Annexin V staining over ABT-263 alone. In xenograft models of these tumors, rapamycin induced a largely cytostatic response in the DoHH-2 and SuDHL-4 models. Coadministration with ABT-263 induced significant tumor regression, with DoHH-2 and SuDHL-4 tumors showing 100% overall response rates. Apoptosis in these tumors was significantly enhanced by combination therapy as measured by staining with an antibody specific for cleaved caspase-3. These data suggest that combination of ABT-263 and rapamycin or its analogues represents a promising therapeutic strategy for the treatment of lymphoma.
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PMID:ABT-263 and rapamycin act cooperatively to kill lymphoma cells in vitro and in vivo. 1885 30

von Hippel-Lindau (VHL) disease is caused by germ-line mutations in the VHL tumor suppressor gene and is the most common cause of inherited renal cell carcinoma (RCC). Mutations in the VHL gene also occur in a large majority of sporadic cases of clear-cell RCC, which have high intrinsic resistance to chemotherapy and radiotherapy. Here we show that VHL-deficient RCC cells express lower levels of the proapoptotic Bcl-2 family protein BIM(EL) and are more resistant to etoposide and UV radiation-induced death compared to the same cells stably expressing the wild-type VHL protein (pVHL). Reintroducing pVHL into VHL-null cells increased the half-life of BIM(EL) protein without affecting its mRNA expression, and overexpressing pVHL inhibited BIM(EL) polyubiquitination. Suppressing pVHL expression with RNA interference resulted in a decrease in BIM(EL) protein and a corresponding decrease in the sensitivity of RCC cells to apoptotic stimuli. Directly inhibiting BIM(EL) expression in pVHL-expressing RCC cells caused a similar decrease in cell death. These results demonstrate that pVHL acts to promote BIM(EL) protein stability in RCC cells, and that destabilization of BIM(EL) in the absence of pVHL contributes to the increased resistance of VHL-null RCC cells to certain apoptotic stimuli.
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PMID:The von Hippel-Lindau protein sensitizes renal carcinoma cells to apoptotic stimuli through stabilization of BIM(EL). 1930 26

The lack of effective anti-tumor therapy for renal cell carcinoma (RCC) has stimulated the search for novel target whose inhibition could block tumorigenesis. Recently, reduced DLC-1 has been shown to be associated with aggressive and highly metastatic renal cell carcinoma. In this study, the biological role of DLC-1 on cell growth, migration and cell cycle progression in RCC cells was investigated. Over-expression of DLC-1 was associated with a marked inhibition of cell growth (P<0.01). The inhibitory effect was partly due to the induction of apoptosis and cell cycle arrest in G(0)/G(1) accompanied by up-regulation of the intracellular signal proteins of p27 and down-regulation of cyclin D1 and cyclin E. Furthermore, DLC-1 induced FAK dephosphorylation of focal adhesion proteins inhibited cell migration (P<0.05). Decreased DLC-1 expression strongly correlated with proliferative activity, as indicated by the elevated levels of Ki67. Restoration of DLC-1 expression in RCC cells led to Bcl-2 and caspase-3 mediated apoptosis as well as attenuated the ability of the cells to form RCC tumors in athymic nude mice (P<0.05). Taken together, these results suggest that DLC-1 plays a crucial role in signal transduction pathway regulating the cell proliferation, migration, and carcinogenesis of human RCC.
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PMID:Overexpression of DLC-1 induces cell apoptosis and proliferation inhibition in the renal cell carcinoma. 1938 Jan 90

Apoptosis and autophagic cell deaths are programmed cell deaths and they play essential roles in cell survival, growth and development and tumorigenesis. The huge increase of publications in both apoptosis and autophagic signaling pathways has contributed to the wealth of knowledge in facilitating the understanding of cancer pathogenesis. Deciphering the molecular pathways and molecules involved in these pathways has helped scientists devise and develop targeted strategies against cancer. Various drugs targeting the apoptotic TRAIL, Bcl-2 and proteasome pathways are already in Phase II/III clinical trials. The first mTOR inhibitor, temsirolimus has already been approved by the FDA, USA for the treatment of advanced renal cell carcinoma and more mTOR inhibitors are expected to be in the market in a few years time. Strategizing against aberrant autophagy activities in various cancers by using either pro-autophagics or autophagy inhibitors are currently been investigated. This review aims to discuss the most recent antitumor strategies targeting the apoptosis and autophagy signaling pathways and the latest outcome of clinical trials of the above drugs.
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PMID:Programmed cell death pathways and current antitumor targets. 1940 32


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