Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1140680 (ovarian cancer)
 28,141 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

BRCA1, a tumor suppressor protein implicated in hereditary forms of breast and ovarian cancer, is transcriptionally regulated in a proliferation-dependent manner. In this study, we demonstrate a substantial role for proteolysis in regulating the BRCA1 steady-state protein level in several cell lines. N-acetyl-leu-leu-norleucinal (ALLN), an inhibitor of the proteasome, calpain, and cathepsins, caused BRCA1 protein to accumulate in the nucleus of several human breast, prostate, and melanoma cell lines which express low or undetectable basal levels of BRCA1 protein, but not in cells with high basal expression of BRCA1. Protease inhibition did not increase BRCA1 synthesis, nor change its mRNA level, but it dramatically prolonged the protein's half-life. In contrast to ALLN, lactacystin and PS341, two specific proteasome inhibitors, as well as calpastatin peptide and PD150606, two selective calpain inhibitors, had no effect on BRCA1 stability, whereas ALLM, an effective calpain and cathepsin inhibitor but weak proteasome inhibitor, did stimulate accumulation of BRCA1. Moreover, three inhibitors of acidic cysteine proteases, chloroquine, ammonium chloride and bafilomycin, were as effective as ALLN. These results demonstrate that degradation by a cathepsin-like protease in fine balance with BRCA1 transcription is responsible for maintaining the low steady-state level of BRCA1 protein seen in many cancer cells.
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PMID:Regulation of BRCA1 by protein degradation. 1059 48

Physiological cell conditions, such as glucose deprivation and hypoxia, play a role in developing drug resistance in solid tumors. These tumor-specific conditions cause decreased expression of DNA topoisomerase IIalpha (topo IIalpha), rendering cells resistant to topo II-targeted drugs, such as etoposide and doxorubicin. We show here that inhibition of proteasome attenuated drug resistance by inhibiting topo IIalpha depletion induced by glucose starvation and hypoxia. topo IIalpha restoration was seen only at the protein levels, indicating that the topo IIalpha protein depletion occurred through a proteasome-mediated degradation mechanism. The stress-induced etoposide resistance was effectively prevented in vitro by the proteasome inhibitor lactacystin in both intrinsically resistant and sensitive tumor cells (colon cancer HT-29 and ovarian cancer A2780 cells, respectively). Furthermore, lactacystin effectively enhanced the antitumor activity of etoposide in the refractory HT-29 xenograft. These results indicate that lactacystin could serve as a new therapeutic agent to circumvent resistance to topo II-targeted chemotherapy in solid tumors.
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PMID:Proteasome inhibition circumvents solid tumor resistance to topoisomerase II-directed drugs. 1081 Nov 20

The ubiquitin-proteasome pathway plays a critical role in the degradation of several proteins involved in the cell cycle. Dysregulation of this pathway leads to inhibition of cellular proliferation and the induction of apoptosis. Ubiquitination and its downstream consequences have been investigated intensively as targets for the development of drugs for tumour therapy. Here we have investigated the mechanism of apoptosis induced by the proteasome inhibitors MG-132, lactacystin and calpain inhibitor I (ALLN), in the HEK 293 cell line and the ovarian cancer cell lines SKOV3 and OVCAR3. We have found strong caspase-3-like and caspase-6-like activation upon treatment of HEK 293 cells with MG-132. Using a tricistronic expression vector based on a tetracycline-responsive system we generated stable SKOV3 nd OVCAR3 cell lines with inducible expression of pro-caspase-3. Induction of pro-caspase-3 expression in normally growing cells does not induce apoptosis. However, in the presence of the proteasome inhibitors MG-132, lactacystin or ALLN we found that cells overexpressing pro-caspase-3 are rapidly targeted for apoptosis. Our results demonstrate that pro-caspase-3 can sensitise ovarian cancer cells to proteasome inhibitor-induced apoptosis, and a combination of these approaches might be exploited for therapy of ovarian and other cancers.
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PMID:Pro-caspase-3 overexpression sensitises ovarian cancer cells to proteasome inhibitors. 1131 8

Small molecules suppressing proteasome function inhibit the post-translational ubiquitination of selected proteins. Ubiquitin H2A is an example of an abundant chromatin-associated protein that is known to be ubiquitinated, which is important for several proteins involved in the repair of DNA damage. We therefore studied the effect of the proteasome inhibitor, N-acetyl leucyl-leucyl norlucinal (ALLnL), on cisplatin sensitivity in three human ovarian tumor cell lines. The proteasome inhibitor ALLnL was administered for 4 h before cells were subsequently exposed to cisplatin for 1 h. Our results showed that ALLnL, at its respective IC20 concentration, increased cellular sensitivity to cisplatin in an additive manner in human ovarian cancer A2780, A2780/CP70, and OVCAR3 cells. We also demonstrated that ALLnL caused a 50% increase in total cellular accumulation of cisplatin, and reduced the rate of cisplatin efflux by about 50%. In addition, DNA damage levels were increased after ALLnL treatment. By contrast, DNA repair was inhibited 2 to 3-fold in ALLnL-pretreated cells, as compared to the controls. Furthermore, our study showed that ALLnL deubiquitinated nucleosomal histone H2A in these cells in a concentration-dependent fashion, as assessed by Western blot analysis. These data suggest that sublethal levels of exposure to agents that inhibit proteasome function may alter the subcellular pharmacology of platinum in human ovarian carcinoma cells.
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PMID:Effect of the proteasome inhibitor ALLnL on cisplatin sensitivity in human ovarian tumor cells. 1156 49

The ERK1/2 MAPK pathway is a critical signaling system that mediates ligand-stimulated signals for the induction of cell proliferation, differentiation, and cell survival. Studies have shown that this pathway is constitutively active in several human malignancies and may be involved in the pathogenesis of these tumors. In the present study we examined the ERK1/2 pathway in cell lines derived from epithelial and granulosa cell tumors, two distinct forms of ovarian cancer. We show that ERK1 and ERK2 are constitutively active and that this activation results from both MAPK kinase-dependent and independent mechanisms and is correlated with elevated BRAF expression. MAPK phosphatase 1 (MKP-1) expression, which is involved in ERK1/2 deactivation, is down-regulated in the cancer cells, thus further contributing to ERK hyperactivity in these cells. Treatment of these cancer cell lines with the proteasome inhibitor ZLLF-CHO increased MKP-1 but not MKP-2 expression and decreased ERK1/2 phosphorylation. More importantly, silencing of ERK1/2 protein expression using RNA interference led to the complete suppression of tumor cell proliferation. These results provide evidence that the ERK pathway plays a major role in ovarian cancer pathogenesis and that down-regulation of this master signaling pathway is highly effective for the inhibition of ovarian tumor growth.
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PMID:Mechanisms regulating the constitutive activation of the extracellular signal-regulated kinase (ERK) signaling pathway in ovarian cancer and the effect of ribonucleic acid interference for ERK1/2 on cancer cell proliferation. 1524 31

The proteasome inhibitor bortezomib has shown activity in chemotherapy-resistant tumors and is approved for treatment of multiple myeloma. The critical component of bortezomib's antitumor activity is the inhibition of nuclear factor-kappa B (NF-kappaB). Patients with ovarian cancer respond to initial platinum-based chemotherapy, such as cisplatin. However, these agents have been shown to induce tumor cell survival by inducing NF-kappaB activity. Phase I trials of bortezomib in solid tumors, including ovarian cancer, are summarized and examined to determine if the compound can overcome the impact of chemoresistance. In one trial of single-agent bortezomib in advanced malignancies, it was deemed a safe and manageable drug with potential efficacy in solid tumors. A second phase I trial explored inhibition of NF-kappaB with bortezomib to see if the drug rendered platinum agents more sensitive in ovarian cancer patients. Seven of the nine patients in the study had major responses to the combination of carboplatin and bortezomib. The two trials indicate promising results for bortezomib in patients with solid tumors and patients with recurrent ovarian cancer, but further investigation is warranted.
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PMID:Clinical update: novel targets in gynecologic malignancies. 1579 41

Proteasome inhibitors have emerged as promising anticancer therapeutic agents. Bortezomib (PS-341), a specific proteasome inhibitor, exhibits antitumor activity against a wide range of malignancies and has been approved by the US Food and Drug Administration for the treatment of relapsed or refractory multiple myeloma. However, the molecular mechanisms of bortezomib-mediated apoptosis remain unclear. To characterize the mechanisms of apoptosis induction by proteasome inhibitors, we examined levels of Bcl-2 protein family members (Bik/NBK, Bax, Bak, Bcl-2, and Bcl-XL), release of cytochrome c, and activation of caspase-9 and -3 in human colon cancer cell lines DLD1, LOVO, SW620, and HCT116; human lung cancer cell line H1299; and human ovarian cancer cell line SKOV3 after they were treated with bortezomib. The result showed that bortezomib induced rapid accumulation of Bik/NBK but not other Bcl-2 family members in all six cell lines. Bortezomib-mediated Bik/NBK accumulation and apoptosis were also observed in human embryonic kidney cells 293 and normal human bronchial epithelial cells. Moreover, dramatic Bik/NBK accumulation and apoptosis induction were observed when cells were treated with proteasome inhibitor MG132 and calpain inhibitor I (ALLN). Furthermore, no detectable changes in IkappaBalpha levels or in NFkappaB functionality were found after treatment with bortezomib. Finally, Bik/NBK accumulation was caused by stabilization of the protein from degradation and was associated with bortezomib cytotoxicity and apoptosis induction. Pretreatment of DLD1 cells with Bik/NBK siRNA reduced bortezomib-mediated Bik/NBK accumulation and cell death. Our results suggested that Bik/NBK is one of the mediators of proteasome inhibitor-induced apoptosis.
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PMID:Bik/NBK accumulation correlates with apoptosis-induction by bortezomib (PS-341, Velcade) and other proteasome inhibitors. 1582 29

A major challenge in cancer therapy is tumor drug resistance. To overcome it, it is essential to understand the mechanisms and identify the molecules involved, so that they can be specifically targeted in combination therapies. The proteasome is such a validated target: it plays a key role in cancer cell proliferation, inhibition of chemotherapy-induced apoptosis and drug resistance development. Bortezomib (Velcade, PS-341) was the first proteasome inhibitor to receive regulatory approval from the US Food and Drug Administration for the treatment of multiple myeloma. Clinical combination trials have demonstrated a chemo-sensitizing effect of bortezomib on conventional agents in hematological malignancies and some solid tumors such as androgen-independent prostate and ovarian cancer. Although generally well-tolerated, bortezomib still generates toxicity which underscores the need for less toxic proteasome inhibitors. Several naturally occurring products, such as green tea polyphenols and the antibiotic lactacystin, have been shown to be potent proteasome inhibitors. Significantly, green tea polyphenols, as well as several flavonoids such as genistein, curcumin and resveratrol, have also been shown to have chemo-sensitizing properties in prostate, breast, hepatic, and lung tumors. Further studies on natural proteasome inhibitors as chemo-sensitizers could lead to identification of more potent and less toxic compounds that could be used in combination therapies for drug-resistant tumors.
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PMID:The proteasome as a potential target for novel anticancer drugs and chemosensitizers. 1719 31

Melphalan is an alkylating agent approved for the treatment of multiple myeloma and ovarian cancer. The combination of oral melphalan and prednisone was first introduced in the 1960s and remains the standard therapy for elderly multiple myeloma patients. High-dose melphalan followed by autologous stem cell support became the standard treatment for younger patients since the 1990s. The occurrence of drug resistance is the major limiting factor for the long-term success of this therapy, and relapse always occurs. In recent years, advances in the understanding of the pathogenesis of myeloma and the mechanism of drug resistance have led to the development of novel targeted therapies that are able to overcome resistance and show additive or synergistic effects with melphalan. Thalidomide, its immunomodulatory derivative lenalidomide and the proteasome inhibitor bortezomib, in combination with oral melphalan in the elderly and with intravenous melphalan in younger patients, are changing the traditional treatment paradigm of multiple myeloma.
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PMID:Melphalan and its role in the management of patients with multiple myeloma. 1762 53

Resistance of tumors to cell death signals poses a complex clinical problem. In the present study, we have explored the capacity of proteasome inhibitors to induce cell death of ovarian cancer cells. We explored the sensitivity of primary ovarian cancer cells to a combination of bortezomib (also known as PS-341), a proteasome inhibitor and TRAIL, a death ligand, or mapatumumab or lexatumumab, TRAIL-R1 or TRAIL-R2 targeting agonist monoclonal antibodies, respectively. The results of our study showed that the large majority of primary ovarian cancers are clearly sensitive to the pro-apoptotic action of bortezomib, whose effects are potentiated by the concomitant addition of TRAIL or mapatumumab or lexatumumab. Interestingly, both cisplatin and paclitaxel-chemosensitive and chemoresistant ovarian tumors are equally sensitive to the cytotoxic effect of bortezomib. Bortezomib, combined with TRAIL or TRAIL-R1 or TRAIL-R2 agonist monoclonal antibodies may be a useful treatment for refractory ovarian cancer.
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PMID:Primary ovarian cancer cells are sensitive to the proaptotic effects of proteasome inhibitors. 2012 91


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