scholarly journals C6-ceramide treatment inhibits the proangiogenic activity of multiple myeloma exosomes via the miR-29b/Akt pathway

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Liping Liu ◽  
Qinmao Ye ◽  
Langni Liu ◽  
Ji Chen Bihl ◽  
Yanfang Chen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Akt Pathway ◽  
C6 Ceramide

scholarly journals C6-ceramide treatment inhibits the proangiogenic activity of multiple myeloma exosomes via the miR-29b/Akt pathway

2020 ◽  
Author(s):  
Liping Liu ◽  
Qinmao Ye ◽  
Langni Liu ◽  
Ji Chen Bihl ◽  
Yanfang Chen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Underlying Mechanism ◽  
Tube Formation ◽  
Akt Pathway ◽  
Pathological Angiogenesis ◽  
Protein Expressions ◽  
Angiogenic Effect ◽  
C6 Ceramide ◽  
Rpmi 8226

Abstract Background: The increased bone marrow angiogenesis is involved in the progression of multiple myeloma (MM) with the underlying mechanism poorly understood. Cancer-released exosomes could play an important role in the pathological angiogenesis through exosomal microRNAs (miRs) delivery. MiR-29b has been reported in regulating the tumor angiogenesis. Methods: In this study, we explored the role of C6-ceramide (C6-cer, a Ceramide pathway activator) in the angiogenic effect of MM exosomes and its potential mechanism. MM cells (OPM2 and RPMI-8226) treated with C6-cer were studied for its effects on the endothelial cell (EC) functions . Results: Our results showed that exosomes released from MM cells treated by C6-cer ( Exo C6-cer ) significantly inhibited the proliferation, migration and tube formation of ECs. For mechanism studies, we found that the level of miR-29b was increased in ECs treated by exo C6-cer , while mRNA and protein expressions of Akt3, PI3K and VEGFA were decreased in ECs, indicating the involvement of Akt pathway. Furthermore, downregulation of miR-29b by inhibitor administration could prevent the exo C6-cer -induced cell proliferation, migration and angiogenesis of ECs, accompanied with the increased expressions of Akt3, PI3K and VEGFA. Conclusions: Collectively, our data suggest that exo C6-cer -mediated miR-29b expression participates in the progression of MM through suppressing the proliferation, migration and angiogenesis of ECs by targeting Akt signal pathway.

scholarly journals C6-ceramide treatment inhibits the proangiogenic activity of multiple myeloma exosomes via the miR-29b/Akt pathway

2020 ◽  
Author(s):  
Liping Liu ◽  
Qinmao Ye ◽  
Langni Liu ◽  
Ji Chen Bihl ◽  
Yanfang Chen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Underlying Mechanism ◽  
Tube Formation ◽  
Akt Pathway ◽  
Pathological Angiogenesis ◽  
Protein Expressions ◽  
Angiogenic Effect ◽  
C6 Ceramide ◽  
Rpmi 8226

Abstract Background: The increased bone marrow angiogenesis is involved in the progression of multiple myeloma (MM) with the underlying mechanism poorly understood. Cancer-released exosomes could play an important role in the pathological angiogenesis through exosomal microRNAs (miRs) delivery. MiR-29b has been reported in regulating the tumor angiogenesis. Methods: In this study, we explored the role of C6-ceramide (C6-cer, a Ceramide pathway activator) in the angiogenic effect of MM exosomes and its potential mechanism. MM cells (OPM2 and RPMI-8226) treated with C6-cer were studied for its effects on the endothelial cell (EC) functions . Results: Our results showed that exosomes released from MM cells treated by C6-cer ( Exo C6-cer ) significantly inhibited the proliferation, migration and tube formation of ECs. For mechanism studies, we found that the level of miR-29b was increased in ECs treated by exo C6-cer , while mRNA and protein expressions of Akt3, PI3K and VEGFA were decreased in ECs, indicating the involvement of Akt pathway. Furthermore, downregulation of miR-29b by inhibitor administration could prevent the exo C6-cer -induced cell proliferation, migration and angiogenesis of ECs, accompanied with the increased expressions of Akt3, PI3K and VEGFA. Conclusions: Collectively, our data suggest that exo C6-cer -mediated miR-29b expression participates in the progression of MM through suppressing the proliferation, migration and angiogenesis of ECs by targeting Akt signal pathway.

The oral protein-kinase Cβinhibitor enzastaurin (LY317615) suppresses signalling through the AKT pathway, inhibits proliferation and induces apoptosis in multiple myeloma cell lines

2008 ◽  
Vol 49 (7) ◽  
pp. 1374-1383 ◽  
Author(s):  
Antonino Neri ◽  
Sandra Marmiroli ◽  
Pierfrancesco Tassone ◽  
Luigia Lombardi ◽  
Lucia Nobili ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Protein Kinase ◽  
Cell Lines ◽  
Myeloma Cell ◽  
Akt Pathway ◽  
Multiple Myeloma Cell

Enzastaurin (LY317615), an Oral Protein Kinase C β Inhibitor, Induces Apoptosis in Multiple Myeloma Cell Lines.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1577-1577
Author(s):  
Mujahid A. Rizvi ◽  
Kulsoom Ghias ◽  
Katharine M. Davies ◽  
Chunguang Ma ◽  
Nancy L. Krett ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Cell Line ◽  
Cell Lines ◽  
Cancer Cell Line ◽  
Colon Cancer Cell Line ◽  
Myeloma Cell ◽  
Akt Pathway ◽  
Kinase C

Abstract The protein kinase C (PKC) family consists of 11 serine/threonine protein kinase isoforms that are involved with cell proliferation and differentiation, gene transcription, and tumor-induced angiogenesis. The PKC pathway has been shown to play a role in the regulation of cell growth in several hematologic malignancies. However, in multiple myeloma (MM), the role of the PKC pathway has not been extensively studied. Enzastaurin (LY317615), an acyclic bisindolylmaleimide, is an oral inhibitor of the PKC β isozyme. Enzastaurin has been reported to induce apoptosis and suppress proliferation in the HCT116 colon cancer cell line by inhibiting the AKT pathway. The objective of this study was to assess the efficacy of Enzastaurin in inducing apoptosis in MM cell lines and to investigate possible mechanisms of apoptosis. A spectrum of MM cell lines, with unique characteristics (dexamethasone-sensitive, dexamethasone-resistant, chemotherapy-sensitive, chemotherapy-resistant) were treated with Enzastaurin. There is evidence of cell death in all cell lines at clinically significant concentrations (1–3μM) after 72 hours of treatment. The dexamethasone-sensitive MM1.S cell line was used to further assess the effect of Enzastaurin in the presence of dexamethasone, insulin-like growth factor-1 (IGF-1), and IL-6. IGF-1 and IL-6 are potent growth factors for MM and have been observed to blunt the cytotoxic activity of dexamethasone. Dexamethasone and Enzastaurin appear to have an additive effect in the induction of apoptosis. In addition, while IGF-1 slightly decreases the effect of Enzastaurin, IL-6 has no effect. Enzastaurin treatment also induces a decrease in GSK3β and AKTSerine473 phosphorylation. GSK3β phosphorylation is thought to be a reliable pharmacodynamic marker for Enzastaurin activity. In conclusion, these data indicate that Enzastaurin induces apoptosis in MM cells and suppression of the AKT pathway may be one of the mechanisms by which Enzastaurin exerts its anti-myeloma activity.

AKT Dependent and AKT Independent Multiple Myeloma: Heterogeneity in Tumor Cell Signaling.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1511-1511
Author(s):  
Angela Zöllinger ◽  
Thorsten Stühmer ◽  
Manik Chatterjee ◽  
Ralf C. Bargou
Keyword(s):  
Multiple Myeloma ◽  
Tumor Cell ◽  
Cell Line ◽  
Cell Lines ◽  
Specific Inhibitor ◽  
Akt Signaling ◽  
Akt Pathway ◽  
Special Role ◽  
Phosphorylated Akt ◽  
Pharmacologic Inhibition

Abstract The PI3K/Akt pathway has been reported to critically contribute to survival and malignant growth of multiple myeloma (MM). Because most of these data are based on pharmacologic inhibition it is not clear if the effects are due to Akt inhibition or off-target effects. Furthermore, the Akt family of kinases consists of three highly homologous isoforms, that may, nonetheless, display individual functional properties. We therefore conducted siRNA experiments to evaluate if any single isoform posesses a special role for the viability of MM cells. This was complemented with extensive analyses into the functional and signaling properties of the Akt pathway in primary MM cells (n = 30). Our knock-down experiments revealed that in MM.1S, an MM cell line with constitutive phospho-Akt signaling, Akt1 and Akt2 both contributed to MM cell survival whereas Akt3 seemed to be of less relevance. Conversely, survival of MM cell line AMO-1 which has no constitutive phospho-Akt signal was completely unaffected. Treatment of these MM cell lines with the Akt1 and Akt2 specific inhibitor Akti-1/2 showed that this drug totally abolished the phospho-Akt signal in MM.1S at a concentration of 10 microM. Again, MM.1S cells underwent apoptosis whereas AMO-1 cells were resistant. Next, we analyzed Akt signaling in a large panel of primary MM samples. Phosphorylated Akt was determined with intracellular staining and flow cytometry analysis in primary tumor samples and could be detected in about 60% of MM cases. This constitutive signal could be blocked with Akti-1/2 in the presence and absence of bone marrow stromal cells. Pharmacologic inhibition of Akt led to strong induction of cell death in 46% of primary MM samples, whereas the rest was largely resistant to Akt inhibition. The samples sensitive to Akt inhibition were mostly identical to those that displayed a constitutive phospho-Akt signal. Of interest, there was no correlation between Akt dependence and mutational inactivation of PTEN. Further inhibition of other signaling cascades implicated in growth and survival of MM cells, such as the MAPK or STAT3 pathways, had only minor additional effects on tumor cell viability of samples resistant to Akt inhibition. Our analysis indicates substantial heterogeneity in MM cells that defines Akt dependent and Akt independent MM subgroups. Akt1 and Akt2 proved relevant for the survival of subsets of MM cell lines and primary samples. Taken together, this is the first comprehensive functional and molecular signaling analysis of primary MM samples which led to the identification of novel functionally defined myeloma subgroups.

scholarly journals PSAT1 prompted cell proliferation and inhibited cell apoptosis in multiple myeloma through regulating PI3K/AKT pathway

2020 ◽  
Vol 19 (4) ◽  
pp. 745-749
Author(s):  
Hongqing Zhu ◽  
Yejun Si ◽  
Yun Zhuang ◽  
Meng Li ◽  
Jianmin Ji ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Proliferation ◽  
Cell Apoptosis ◽  
Underlying Mechanism ◽  
Akt Pathway ◽  
Protein Levels ◽  
Phosphoserine Aminotransferase ◽  
Proliferation And Apoptosis ◽  
Mrna And Protein Expression ◽  
Polymerase Chain

Purpose: To identify the biological function of phosphoserine aminotransferase 1 (PSAT1) in regulating cell proliferation and apoptosis in multiple myeloma (MM).Methods: The mRNA and protein levels of PSAT1 were determined using quantitative real-time polymerase chain reaction (PCR) and western blotting, respectively. Cell proliferation was measured using CCK-8 assay.Results: PSAT1 mRNA and protein expression levels were significantly increased in MM cell lines when compared to control cells. Moreover,  downregulation of PSAT1 inhibited MM cell proliferation and induced cell apoptosis, whereas overexpression of PSAT1 promoted MM cell  proliferation and suppressed cell apoptosis. Further analysis demonstrated that the underlying mechanism was via regulation of PI3K/AKT pathway.Conclusion: The results identified a novel role for PSAT1 in the progression of MM, which may provide a therapeutic and a new anticancer target for the therapy of MM. Keywords: Multiple myeloma, PSAT1, Cell proliferation, PI3K/AKT pathway

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