Cisplatin increases B-cell-lymphoma-2 expression via activation of protein kinase C and Akt2 in endometrial cancer cells

2011 ◽  
Vol 130 (8) ◽  
pp. 1755-1767 ◽  
Author(s):  
Alexandre Rouette ◽  
Sophie Parent ◽  
Julie Girouard ◽  
Valérie Leblanc ◽  
Eric Asselin
Keyword(s):  
Endometrial Cancer ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
B Cell ◽  
Cancer Cells ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Kinase C

Protein kinase C–associated kinase is required for NF-κB signaling and survival in diffuse large B-cell lymphoma cells

Blood ◽  
2008 ◽  
Vol 111 (3) ◽  
pp. 1644-1653 ◽  
Author(s):  
Sang-Woo Kim ◽  
David W. Oleksyn ◽  
Randall M. Rossi ◽  
Craig T. Jordan ◽  
Ignacio Sanz ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
B Cell ◽  
Cancer Cells ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Chemotherapeutic Agents ◽  
Kinase C ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Diffuse large B-cell lymphoma (DLBCL) is an aggressive and the most common type of non-Hodgkin lymphoma. Despite recent advances in treatment, less than 50% of the patients are cured with current multiagent chemotherapy. Abnormal NF-κB activity not only contributes to tumor development but also renders cancer cells resistant to chemotherapeutic agents. Identifying and targeting signaling molecules that control NF-κB activation in cancer cells may thus yield more effective therapy for DLBCL. Here, we show that while overexpression of protein kinase C–associated kinase (PKK) activates NF-κB signaling in DLBCL cells, suppression of PKK expression inhibits NF-κB activity in these cells. In addition, we show that NF-κB activation induced by B cell–activating factor of tumor necrosis factor family (BAFF) in DLBCL cells requires PKK. Importantly, we show that knockdown of PKK impairs the survival of DLBCL cells in vitro and inhibits tumor growth of xenografted DLBCL cells in mice. Suppression of PKK expression also sensitizes DLBCL cells to treatment with chemotherapeutic agents. Together, these results indicate that PKK plays a pivotal role in the survival of human DLBCL cells and represents a potential target for DLBCL therapy.

scholarly journals Prognostic impact of protein kinase C β II expression in R-CHOP-treated diffuse large B-cell lymphoma patients

2010 ◽  
Vol 23 (5) ◽  
pp. 686-693 ◽  
Author(s):  
Sari Riihijärvi ◽  
Satu Koivula ◽  
Heidi Nyman ◽  
Karin Rydström ◽  
Mats Jerkeman ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Prognostic Impact ◽  
Kinase C ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Protein kinase C-betaII expression in diffuse large B-cell lymphoma predicts for inferior outcome of anthracycline-based chemotherapy with and without rituximab

2009 ◽  
Vol 50 (10) ◽  
pp. 1666-1675 ◽  
Author(s):  
Kritika Chaiwatanatorn ◽  
Georgia Stamaratis ◽  
Ken Opeskin ◽  
Frank Firkin ◽  
Harshal Nandurkar
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Kinase C ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Phase II Study of Enzastaurin, a Protein Kinase C Beta Inhibitor, in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma

2007 ◽  
Vol 25 (13) ◽  
pp. 1741-1746 ◽  
Author(s):  
Michael J. Robertson ◽  
Brad S. Kahl ◽  
Julie M. Vose ◽  
Sven de Vos ◽  
Mary Laughlin ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
B Cell ◽  
Phase Ii Study ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Kinase C ◽  
Large B Cell Lymphoma ◽  
Grade 3 ◽  
Large B Cell

PurposeProtein kinase C beta (PKCβ) was identified by gene-expression profiling, preclinical evaluation, and independent immunohistochemical analysis as a rational therapeutic target in diffuse large B-cell lymphoma (DLBCL). We conducted a multicenter phase II study of a potent inhibitor of PKCβ, enzastaurin, in patients with relapsed or refractory DLBCL.Patients and MethodsEnzastaurin was taken orally once daily until disease progression or unacceptable toxicity occurred. Study end points included freedom from progression (FFP) for ≥ two cycles (one cycle = 28 days), objective response, and toxicity.ResultsFifty-five patients (median age, 68 years) were enrolled. Patients had received a median number of two prior therapies (range, one to five); six patients relapsed after high-dose therapy and autologous stem-cell transplantation. Only one grade 4 toxicity (hypomagnesemia) occurred. Grade 3 toxicities included fatigue (n = 2), edema (n = 1), headache (n = 1), motor neuropathy (n = 1), and thrombocytopenia (n = 1). No grade 3 or 4 neutropenia occurred. No deaths or discontinuations due to toxicity were reported. Fifteen patients completed less than one cycle of therapy. Twelve of 55 patients (22%; 95% CI, 13% to 46%) experienced FFP for ≥ two cycles, and eight patients remained free from progression for ≥ four cycles (15%; 95% CI, 6% to 27%). Four patients (7%; 95% CI, 2% to 18%), including three complete responders and one patient with stable disease, continue to experience FFP 20+ to 50+ months after study entry.ConclusionTreatment with enzastaurin was well-tolerated and associated with prolonged FFP in a small subset of patients with relapsed or refractory DLBCL. Further studies of enzastaurin in DLBCL are warranted.

scholarly journals Protein kinase C-independent stimulation of activator protein-1 and c-Jun N-terminal kinase activity in human endometrial cancer cells by the LHRH agonist triptorelin

2001 ◽  
pp. 651-658 ◽  
Author(s):  
C Grundker ◽  
L Schlotawa ◽  
V Viereck ◽  
G Emons
Keyword(s):  
Cell Proliferation ◽  
Endometrial Cancer ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Cancer Cells ◽  
Fold Increase ◽  
Lhrh Agonist ◽  
Activator Protein 1 ◽  
Kinase C ◽  
Lhrh Receptor

OBJECTIVE: The expression of luteinizing hormone-releasing hormone (LHRH) and its receptor as a part of an autocrine regulatory system of cell proliferation has been demonstrated in a number of human malignant tumours, including cancers of the endometrium. The signalling pathway through which LHRH acts in endometrial cancer is distinct from that in pituitary gonadotrophs. The LHRH receptor interacts with the mitogenic signal transduction of growth factor receptors via activation of a phosphotyrosine phosphatase, resulting in down-regulation of cancer cell proliferation. In addition, LHRH activates nucleus factor kappaB (NFkappaB) and protects the cancer cells from apoptosis. This study was conducted to investigate additional signalling mechanisms of the LHRH receptor cooperating with NFkappaB in endometrial cancer cells. DESIGN: The LHRH agonist triptorelin-induced activator protein-1 (AP-1) activation was analysed using a pAP-1-SEAP reporter gene assay. Expression of c-jun mRNA was quantified using quantitative reverse transcription (RT)-PCR. c-Jun N-terminal kinase (JNK) activity was measured by quantification of phosphorylated c-Jun protein. RESULTS: Treatment of Ishikawa and Hec-1A human endometrial cancer cells with 100 nM triptorelin resulted in a 3.1-fold and 3.5-fold activation of AP-1 respectively (P<0.05). If the cells had been made quiescent, treatment with triptorelin (100 nM) resulted in a 41.7-fold and 48.6-fold increase of AP-1 activation respectively (P<0.001). This effect was completely blocked by simultaneous treatment with pertussis toxin (PTX). A 17.6-fold and 17.3-fold increase of c-jun mRNA expression respectively (P<0.001) was obtained after 20 min of stimulation with triptorelin (100 nM). Treatment with 1 nM triptorelin resulted in a 12.5-fold or an 11.9-fold increase, and treatment with 10 pM triptorelin resulted in a 6.5-fold or a 5.2-fold increase of maximal c-jun mRNA expression respectively (P<0.001). Maximal c-Jun phosphorylation (68.5-fold and 60.2-fold, respectively, P<0.001) was obtained after 90 min incubation with triptorelin (100 nM). CONCLUSIONS: These results suggest that the LHRH agonist triptorelin stimulates the activity of AP-1 in human endometrial cancer cells mediated through PTX-sensitive G-protein alphai. In addition, triptorelin activates JNK, known to activate AP-1. In earlier investigations we have shown that triptorelin does not activate phospholipase and protein kinase C (PKC) in endometrial cancer cells. In addition, it has been demonstrated that triptorelin inhibits growth factor-induced mitogen activated protein kinase (MAPK, ERK) activity. Thus triptorelin-induced activation of the JNK/AP-1 pathway in endometrial cancer cells is independent of the known AP-1 activators, PKC or MAPK (ERK).

scholarly journals Protein kinase C β inhibits autophagy and sensitizes cervical cancer Hela cells to cisplatin

2017 ◽  
Vol 37 (2) ◽  
Author(s):  
Na Li ◽  
Wei Zhang
Keyword(s):  
Cervical Cancer ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Cancer Cells ◽  
Hela Cells ◽  
B Cell Lymphoma ◽  
Kinase C ◽  
Cervical Cancer Cells ◽  
Pkc Β ◽  
Induced Apoptosis

Recently, autophagy has been indicated to play an essential role in various biological events, such as the response of cervical cancer cells to chemotherapy. However, the exact signalling mechanism that regulates autophagy during chemotherapy remains unclear. In the present study, we investigated the regulation by cisplatin on protein kinase C β (PKC β), on B-cell lymphoma 2 (Bcl-2) and on apoptosis in cervical cancer Hela cells. And then we examined the regulation by cisplatin on autophagy and the role of autophagy on the chemotherapy in Hela cells. In addition, the regulation of the PKC β on the autophagy was also investigated. Our results indicated that cisplatin promoted PKC β in Hela cells. The PKC β inhibitor reduced the cisplatin-induced apoptosis, whereas increased the cisplatin-induced autophagy in Hela cells. On the other side, the PKC β overexpression aggravated the cisplatin-induced apoptosis, whereas down-regulated the cisplatin-induced autophagy. Taken together, our study firstly recognized the involvement of PKC β in the cytotoxicity of cisplatin via inhibiting autophagy in cervical cancer cells. We propose that PKC β would sensitize cervical cancer cells to chemotherapy via reducing the chemotherapy induced autophagy in cancer cells.

Inhibition of Protein Kinase C beta by Enzastaurin (LY 317615) Induces Alterations of Key Regulators of Cell Cycle and Apoptosis in Mantle Cell Lymphoma and Synergizes with Chemotherapeutic Agents in a Sequence Dependent Manner.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2416-2416 ◽  
Author(s):  
Malte Rieken ◽  
Oliver Weigert ◽  
Alessandro Pastore ◽  
Grit Hutter ◽  
Yvonne Zimmermann ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Western Blot ◽  
B Cell ◽  
Cell Lines ◽  
Cell Lymphoma ◽  
Dependent Manner ◽  
Kinase C ◽  
Mantle Cell

Abstract Mantle Cell Lymphoma (MCL) is a subtype of malignant lymphoma, characterized by a poor clinical outcome, a median survival time of three years and almost no long-term survivors. In previous studies it could be shown that constitutive overexpression of NFκB pathway plays an important role in the pathogenesis of MCL. The protein kinase C (PKC) family is essential in cell signal regulation effecting cellular growth, proliferation and apoptosis. Previous studies in diffuse large B-cell lymphoma suggest that PKCβ overexpression enhances B-cell proliferation and is associated with poor clinical prognosis. The pivotal role of PKCβ in activation of NFκB renders it a promising therapeutic target in the therapy of MCL. Five MCL cell lines (GRANTA 519, HBL-2, Jeko-1, NCEB-1, Rec-1) and two haematological control cell lines (Jurkat, Karpas 422) were treated with Enzastaurin in a proliferation inhibiting dose of 10μM, defined in initial pilot experiments. Real-time PT-PCR and protein expression (Western blot) levels of various regulators of cell cycle and apoptosis were determined at various time points of enzastaurin treatment (0.5 to 12 hours). In addition analysis of cell cycle and apoptosis were performed by flow-cytometry. All, cell lines were also exposed to different doses of enzastaurin in combination with cytarabine, fludarabine or mitoxantrone and analysed for efficacy by evaluating the combination index. Inhibition of proliferation was achieved in all cell lines in a dose and time-dependent manner, however susceptibility varied strongly within the cell lines characterized by IC 50 (24 hours) ranging from 8,0 μM in Jeko-1 to &gt; 50μM in GRANTA 519, Rec-1 and Karpas 422. Induction of apoptosis was detected in all cell lines according to susceptibility, and cell cycle analysis exhibits a moderate accumulation of and cells in the G2/M phase. Significant alterations of RNA expression was detected for BCL-2, cyclin D1 and p14 applying the Kruskal-Wallis-Test. Preliminary Western blot data confirm the altered levels of protein expressions. Synergistic effects of Enzastaurin combinations were sequence dependent, and resulted in a super-additive effect when the exposure of cells to cytostatic agents was followed by Enzastaurin treatment. No synergy effect was observed in combination with fludarabine. Our study revealed alteration of gene expression, critical for the regulation of cell cycle and apoptosis, after Enzastaurin treatment. Even more important, combination with specific cytostatic drugs demonstrated a synergistic efficacy in vitro. Thus, our data suggest that inhibition of PKCβ can overcome chemotherapy resistance by cellular survival mechanisms supporting the evaluation of such combinations in clinical trials.

Sign in / Sign up

Export Citation Format

Share Document