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Novel Etoposide Analogue Modulates Expression of Angiogenesis Associated microRNAs and Regulates Cell Proliferation by Targeting STAT3 in Breast Cancer.

Srinivas C, Ramaiah MJ, Lavanya A, Yerramsetty S, Kavi Kishor PB, Basha SA, Kamal A, Bhadra U, Bhadra MP - PLoS ONE (2015)

Bottom Line: We developed a novel Etoposide analogue, Quinazolino-4β-amidopodophyllotoxin (C-10) that show better efficacy in regulating cell proliferation and angiogenesis.Docking studies clearly demonstrated the binding of Etoposide and C-10 to STAT3.We conclude that combination of Etoposide or C-10 with miR-15, 16, 17 and 221 as a new approach to induce apoptosis and control angiogenesis in breast cancer.

View Article: PubMed Central - PubMed

Affiliation: Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad, India.

ABSTRACT
Tumor microenvironment play role in angiogenesis and carcinogenesis. Etoposide, a known topoisomerase II inhibitor induces DNA damage resulting in cell cycle arrest. We developed a novel Etoposide analogue, Quinazolino-4β-amidopodophyllotoxin (C-10) that show better efficacy in regulating cell proliferation and angiogenesis. We evaluated its role on expression of microRNAs-15, 16, 17 and 221 and its targets Bcl-2, STAT3 and VEGF that dictate cell proliferation and angiogenesis. Docking studies clearly demonstrated the binding of Etoposide and C-10 to STAT3. We conclude that combination of Etoposide or C-10 with miR-15, 16, 17 and 221 as a new approach to induce apoptosis and control angiogenesis in breast cancer.

No MeSH data available.


Related in: MedlinePlus

C-10 modulates microRNA expression and its biogenesis.(A) Endogenous microRNA expression studies in compound treated MCF-7 and MDA-MB-231 cells showing significant upregulation of miR-15 and miR-16 in Etoposide or C-10 treated cells compared to miR-17 and miR-221. (B) The C-10 compound enhanced the expression of Drosha, Dicer, TRBP and Ago-1 enzymes that involved in synthesis and processing of matured microRNAs. (C) Computational analysis of miRNA prediction shows the possible binding sites in 3’UTR of Bcl-2, STAT3 and VEGFA for each miRNA-15, 16, 17 and 221 along with miSVR scores as depicted by miRanda software.
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pone.0142006.g002: C-10 modulates microRNA expression and its biogenesis.(A) Endogenous microRNA expression studies in compound treated MCF-7 and MDA-MB-231 cells showing significant upregulation of miR-15 and miR-16 in Etoposide or C-10 treated cells compared to miR-17 and miR-221. (B) The C-10 compound enhanced the expression of Drosha, Dicer, TRBP and Ago-1 enzymes that involved in synthesis and processing of matured microRNAs. (C) Computational analysis of miRNA prediction shows the possible binding sites in 3’UTR of Bcl-2, STAT3 and VEGFA for each miRNA-15, 16, 17 and 221 along with miSVR scores as depicted by miRanda software.

Mentions: Recently, microRNAs have emerged as new promising players that control expression of genes involved in various cellular processes. miRNAs regulate angiogenesis by changing the expression of pro and antiangiogenic factors and endothelial cell function. Aberrant expression of miR-15a/16 causes decrease in the expression of VEGF-A and play a vital role in tumorigenesis particularly in Multiple Myeloma (MM) [31–34]. Studies suggest that ectopic expression of miR-17 and miR-221 inhibit cell proliferation and migration by targeting STAT3 and induce apoptosis [35, 36]. In another study, it was evidenced that the Quinazoline based small molecules enhance the global upregulation of microRNAs involved in the process of apoptosis in breast cancer cells [37]. Therefore, we studied the expression pattern of these miRNAs in MCF-7 and MDA-MB-231 breast cancer cell lines. Cells treated with Cisplatin, Etoposide or C-10 were incubated for 24 hours and subjected to endogenous miRNA expression studies. Interestingly, we observed that both Etoposide and C-10 induced significant increase in expression of miRNAs-15 and 16 and also there was a modest increase in expression of miR-17 and 221 (Fig 2A). Studies by different groups reported that small molecules enhance RNA interference and promote microRNA processing by enhancing the expression of TRBP, which is an integral component of Dicer1 complex that plays a critical role in microRNA processing [38, 39]. Therefore, to understand the mechanism underlying the upregulation of these microRNAs, we investigated whether C-10 has any regulatory potential role on expression of microRNA processing enzymes Drosha, Dicer, TRBP and Ago-1 that play a major role in the microRNA biogenesis pathway. We observed that C-10 molecule positively regulate both nuclear microprocessor enzyme Drosha and the cytoplasmic Dicer, TRBP and Ago-1 in MCF-7 and MDA-MB-231 cells (Fig 2B). These observations clearly suggested that C-10 molecule modulated the expression of microRNAs-15, 16, 17 and 221 by inducing microRNA processing machinery.


Novel Etoposide Analogue Modulates Expression of Angiogenesis Associated microRNAs and Regulates Cell Proliferation by Targeting STAT3 in Breast Cancer.

Srinivas C, Ramaiah MJ, Lavanya A, Yerramsetty S, Kavi Kishor PB, Basha SA, Kamal A, Bhadra U, Bhadra MP - PLoS ONE (2015)

C-10 modulates microRNA expression and its biogenesis.(A) Endogenous microRNA expression studies in compound treated MCF-7 and MDA-MB-231 cells showing significant upregulation of miR-15 and miR-16 in Etoposide or C-10 treated cells compared to miR-17 and miR-221. (B) The C-10 compound enhanced the expression of Drosha, Dicer, TRBP and Ago-1 enzymes that involved in synthesis and processing of matured microRNAs. (C) Computational analysis of miRNA prediction shows the possible binding sites in 3’UTR of Bcl-2, STAT3 and VEGFA for each miRNA-15, 16, 17 and 221 along with miSVR scores as depicted by miRanda software.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4638343&req=5

pone.0142006.g002: C-10 modulates microRNA expression and its biogenesis.(A) Endogenous microRNA expression studies in compound treated MCF-7 and MDA-MB-231 cells showing significant upregulation of miR-15 and miR-16 in Etoposide or C-10 treated cells compared to miR-17 and miR-221. (B) The C-10 compound enhanced the expression of Drosha, Dicer, TRBP and Ago-1 enzymes that involved in synthesis and processing of matured microRNAs. (C) Computational analysis of miRNA prediction shows the possible binding sites in 3’UTR of Bcl-2, STAT3 and VEGFA for each miRNA-15, 16, 17 and 221 along with miSVR scores as depicted by miRanda software.
Mentions: Recently, microRNAs have emerged as new promising players that control expression of genes involved in various cellular processes. miRNAs regulate angiogenesis by changing the expression of pro and antiangiogenic factors and endothelial cell function. Aberrant expression of miR-15a/16 causes decrease in the expression of VEGF-A and play a vital role in tumorigenesis particularly in Multiple Myeloma (MM) [31–34]. Studies suggest that ectopic expression of miR-17 and miR-221 inhibit cell proliferation and migration by targeting STAT3 and induce apoptosis [35, 36]. In another study, it was evidenced that the Quinazoline based small molecules enhance the global upregulation of microRNAs involved in the process of apoptosis in breast cancer cells [37]. Therefore, we studied the expression pattern of these miRNAs in MCF-7 and MDA-MB-231 breast cancer cell lines. Cells treated with Cisplatin, Etoposide or C-10 were incubated for 24 hours and subjected to endogenous miRNA expression studies. Interestingly, we observed that both Etoposide and C-10 induced significant increase in expression of miRNAs-15 and 16 and also there was a modest increase in expression of miR-17 and 221 (Fig 2A). Studies by different groups reported that small molecules enhance RNA interference and promote microRNA processing by enhancing the expression of TRBP, which is an integral component of Dicer1 complex that plays a critical role in microRNA processing [38, 39]. Therefore, to understand the mechanism underlying the upregulation of these microRNAs, we investigated whether C-10 has any regulatory potential role on expression of microRNA processing enzymes Drosha, Dicer, TRBP and Ago-1 that play a major role in the microRNA biogenesis pathway. We observed that C-10 molecule positively regulate both nuclear microprocessor enzyme Drosha and the cytoplasmic Dicer, TRBP and Ago-1 in MCF-7 and MDA-MB-231 cells (Fig 2B). These observations clearly suggested that C-10 molecule modulated the expression of microRNAs-15, 16, 17 and 221 by inducing microRNA processing machinery.

Bottom Line: We developed a novel Etoposide analogue, Quinazolino-4β-amidopodophyllotoxin (C-10) that show better efficacy in regulating cell proliferation and angiogenesis.Docking studies clearly demonstrated the binding of Etoposide and C-10 to STAT3.We conclude that combination of Etoposide or C-10 with miR-15, 16, 17 and 221 as a new approach to induce apoptosis and control angiogenesis in breast cancer.

View Article: PubMed Central - PubMed

Affiliation: Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad, India.

ABSTRACT
Tumor microenvironment play role in angiogenesis and carcinogenesis. Etoposide, a known topoisomerase II inhibitor induces DNA damage resulting in cell cycle arrest. We developed a novel Etoposide analogue, Quinazolino-4β-amidopodophyllotoxin (C-10) that show better efficacy in regulating cell proliferation and angiogenesis. We evaluated its role on expression of microRNAs-15, 16, 17 and 221 and its targets Bcl-2, STAT3 and VEGF that dictate cell proliferation and angiogenesis. Docking studies clearly demonstrated the binding of Etoposide and C-10 to STAT3. We conclude that combination of Etoposide or C-10 with miR-15, 16, 17 and 221 as a new approach to induce apoptosis and control angiogenesis in breast cancer.

No MeSH data available.


Related in: MedlinePlus