scholarly journals Selective Targeting of the Hedgehog Signaling Pathway by PBM Nanoparticles in Docetaxel-Resistant Prostate Cancer

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 1976
Author(s):  
Santosh Kumar Singh ◽  
Jennifer B. Gordetsky ◽  
Sejong Bae ◽  
Edward P. Acosta ◽  
James W. Lillard ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Signaling Pathway ◽  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Resistant Disease ◽  
Natural Polysaccharide ◽  
Selective Targeting ◽  
Hh Signaling ◽  
Gli 1 ◽  
Specific Membrane

An abnormality in hedgehog (Hh) signaling has been implicated in the progression of prostate cancer (PCa) to a more aggressive and therapy-resistant disease. Our assessments of human PCa tissues have shown an overexpression of the Hh pathway molecules, glioma-associated oncogene homolog 1 (GLI-1), and sonic hedgehog (SHH). The effect of the natural compound thymoquinone (TQ) in controlling the expression of Hh signaling molecules in PCa was investigated in this study. We generated planetary ball-milled nanoparticles (PBM-NPs) made with a natural polysaccharide, containing TQ, and coated with an RNA aptamer, A10, which binds to prostate-specific membrane antigen (PSMA). We prepared docetaxel-resistant C4-2B-R and LNCaP-R cells with a high expression of Hh, showing the integration of drug resistance and Hh signaling. Compared to free TQ, A10-TQ-PBM-NPs were more effective in controlling the Hh pathway. Our findings reveal an effective treatment strategy to inhibit the Hh signaling pathway, thereby suppressing PCa progression.

scholarly journals Native V. Californicum Alkaloid Combinations Induce Differential Inhibition of Sonic Hedgehog Signaling

2018 ◽  
Author(s):  
Matthew W. Turner ◽  
Roberto Cruz ◽  
Jordan Elwell ◽  
John French ◽  
Jared Mattos ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Plant Part ◽  
Differential Inhibition ◽  
Sonic Hedgehog Signaling ◽  
Alkaloid Composition ◽  
Hh Signaling ◽  
Inhibitory Potential ◽  
Pathway Inhibition

Veratrum californicum is a rich source of steroidal alkaloids such as cyclopamine, a known inhibitor of the Hedgehog (Hh) signaling pathway. Here we provide a detailed analysis of the alkaloid composition of V. californicum by plant part through quantitative analysis of cyclopamine, veratramine, muldamine and isorubijervine in the leaf, stem and root/rhizome of the plant. To determine if additional alkaloids in the extracts contribute to Hh signaling inhibition, we replicated the concentrations of these alkaloids observed in extracts using commercially available standards and compared the inhibitory potential of the extracts to alkaloid standard mixtures using Shh-Light II cells. Alkaloid combinations enhanced Hh signaling pathway antagonism compared to cyclopamine alone, and significant differences were observed in the Hh pathway inhibition between the stem and root/rhizome extracts and their corresponding alkaloid standard mixtures, indicating that additional alkaloids present in these extracts contribute to Hh signaling inhibition.

scholarly journals Transcriptional Regulation ofbcl-2Mediated by the Sonic Hedgehog Signaling Pathway through gli-1

2003 ◽  
Vol 279 (2) ◽  
pp. 1197-1205 ◽  
Author(s):  
Rebecca L. H. Bigelow ◽  
Nikhil S. Chari ◽  
Anne Birgitte Undén ◽  
Kevin B. Spurgers ◽  
Sangjun Lee ◽  
...  
Keyword(s):  
Transcriptional Regulation ◽  
Signaling Pathway ◽  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Hedgehog Signaling Pathway ◽  
Sonic Hedgehog Signaling ◽  
Sonic Hedgehog Signaling Pathway ◽  
Gli 1

scholarly journals p63 sustains self-renewal of mammary cancer stem cells through regulation of Sonic Hedgehog signaling

2015 ◽  
Vol 112 (11) ◽  
pp. 3499-3504 ◽  
Author(s):  
Elisa Maria Memmi ◽  
Anna Giulia Sanarico ◽  
Arianna Giacobbe ◽  
Angelo Peschiaroli ◽  
Valentina Frezza ◽  
...  
Keyword(s):  
Stem Cell ◽  
Signaling Pathway ◽  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Breast Tumorigenesis ◽  
Sonic Hedgehog Signaling ◽  
Self Renewal ◽  
Genes Encoding ◽  
Hh Signaling

The predominant p63 isoform, ΔNp63, is a master regulator of normal epithelial stem cell (SC) maintenance. However, in vivo evidence of the regulation of cancer stem cell (CSC) properties by p63 is still limited. Here, we exploit the transgenic MMTV-ErbB2 (v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2) mouse model of carcinogenesis to dissect the role of p63 in the regulation of mammary CSC self-renewal and breast tumorigenesis. ErbB2 tumor cells enriched for SC-like properties display increased levels of ΔNp63 expression compared with normal mammary progenitors. Down-regulation of p63 in ErbB2 mammospheres markedly restricts self-renewal and expansion of CSCs, and this action is fully independent of p53. Furthermore, transplantation of ErbB2 progenitors expressing shRNAs against p63 into the mammary fat pads of syngeneic mice delays tumor growth in vivo. p63 knockdown in ErbB2 progenitors diminishes the expression of genes encoding components of the Sonic Hedgehog (Hh) signaling pathway, a driver of mammary SC self-renewal. Remarkably, p63 regulates the expression of Sonic Hedgehog (Shh), GLI family zinc finger 2 (Gli2), and Patched1 (Ptch1) genes by directly binding to their gene regulatory regions, and eventually contributes to pathway activation. Collectively, these studies highlight the importance of p63 in maintaining the self-renewal potential of mammary CSCs via a positive modulation of the Hh signaling pathway.

scholarly journals Native V. californicum Alkaloid Combinations Induce Differential Inhibition of Sonic Hedgehog Signaling

Molecules ◽  
2018 ◽  
Vol 23 (9) ◽  
pp. 2222 ◽  
Author(s):  
Matthew Turner ◽  
Roberto Cruz ◽  
Jordan Elwell ◽  
John French ◽  
Jared Mattos ◽  
...  
Keyword(s):  
Quantitative Analysis ◽  
Signaling Pathway ◽  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Plant Part ◽  
Differential Inhibition ◽  
Sonic Hedgehog Signaling ◽  
Alkaloid Composition ◽  
Hh Signaling ◽  
Pathway Inhibition

Veratrum californicum is a rich source of steroidal alkaloids such as cyclopamine, a known inhibitor of the Hedgehog (Hh) signaling pathway. Here we provide a detailed analysis of the alkaloid composition of V. californicum by plant part through quantitative analysis of cyclopamine, veratramine, muldamine and isorubijervine in the leaf, stem and root/rhizome of the plant. To determine whether additional alkaloids in the extracts contribute to Hh signaling inhibition, the concentrations of these four alkaloids present in extracts were replicated using commercially available standards, followed by comparison of extracts to alkaloid standard mixtures for inhibition of Hh signaling using Shh-Light II cells. Alkaloid combinations enhanced Hh signaling pathway antagonism compared to cyclopamine alone, and significant differences were observed in the Hh pathway inhibition between the stem and root/rhizome extracts and their corresponding alkaloid standard mixtures, indicating that additional alkaloids present in these extracts are capable of inhibiting Hh signaling.

The Adventures of Sonic Hedgehog in Development and Repair. I. Hedgehog signaling in gastrointestinal development and disease

2008 ◽  
Vol 294 (2) ◽  
pp. G363-G367 ◽  
Author(s):  
Caroline A. Parkin ◽  
Philip W. Ingham
Keyword(s):  
Signaling Pathway ◽  
Early Development ◽  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Mechanisms Of Action ◽  
Gi Tract ◽  
Hh Signaling

Hedgehog (Hh) proteins are members of a family of secreted signaling factors that orchestrate the development of many organs and tissues including those of the gastrointestinal (GI) tract. The requirement for Hh activity is not limited to early development but underlies the homeostasis of a number of tissues, and abnormal activity of the Hh pathway is associated with several GI malignancies. Understanding the roles and mechanisms of action of Hh signaling both in development and postnatally should thus give novel insights into potential treatments for these diseases. Here we focus on the Hh signaling pathway and its role in GI tract development and maintenance and consider the diseases resulting from aberrant Hh activity.

scholarly journals The Role of Sonic Hedgehog-Gli2 Pathway in the Masculinization of External Genitalia

Endocrinology ◽  
2011 ◽  
Vol 152 (7) ◽  
pp. 2894-2903 ◽  
Author(s):  
Shinichi Miyagawa ◽  
Daisuke Matsumaru ◽  
Aki Murashima ◽  
Akiko Omori ◽  
Yoshihiko Satoh ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
External Genitalia ◽  
Sexually Dimorphic ◽  
Hedgehog Signaling Pathway ◽  
Initial Development ◽  
Urethral Plate ◽  
Male External Genitalia

During embryogenesis, sexually dimorphic organogenesis is achieved by hormones produced in the gonad. The external genitalia develop from a single primordium, the genital tubercle, and their masculinization processes depend on the androgen signaling. In addition to such hormonal signaling, the involvement of nongonadal and locally produced masculinization factors has been unclear. To elucidate the mechanisms of the sexually dimorphic development of the external genitalia, series of conditional mutant mouse analyses were performed using several mutant alleles, particularly focusing on the role of hedgehog signaling pathway in this manuscript. We demonstrate that hedgehog pathway is indispensable for the establishment of male external genitalia characteristics. Sonic hedgehog is expressed in the urethral plate epithelium, and its signal is mediated through glioblastoma 2 (Gli2) in the mesenchyme. The expression level of the sexually dimorphic genes is decreased in the glioblastoma 2 mutant embryos, suggesting that hedgehog signal is likely to facilitate the masculinization processes by affecting the androgen responsiveness. In addition, a conditional mutation of Sonic hedgehog at the sexual differentiation stage leads to abnormal male external genitalia development. The current study identified hedgehog signaling pathway as a key factor not only for initial development but also for sexually dimorphic development of the external genitalia in coordination with androgen signaling.

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