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NVP-LDE-225 (Erismodegib) inhibits epithelial-mesenchymal transition and human prostate cancer stem cell growth in
1Department of Pharmacology, Toxicology and Therapeutics, and Medicine, The University of Kansas Cancer Center, The University of Kansas Medical Center, Kansas City, KS, USA.
Abstract:
Prostate cancer stem cells (CSCs) are defined by their extensive self-renewal, differentiation and tumor initiation properties. It is now clear that CSCs are involved in tumor growth and recurrence, and resistance to conventional treatments. The sonic hedgehog (Shh) pathway has a crucial role in stemness and tumorigenesis. Thus, the strategy that suppresses stemness and consequently tumorigenic potential of CSCs could be considered for the management of prostate cancer. The objectives of this study were to examine the molecular mechanisms, by which NVP-LDE-225/Erismodegib (smoothened inhibitor) regulates stem cell characteristics and tumor growth in prostate cancer. The effects of NVP-LDE-225 on CSC's viability, sphere formation, apoptosis, epithelial-mesenchymal transition (EMT) and tumor growth in NOD/SCID IL2Rγ null mice were examined. NVP-LDE-225 inhibited cell viability and spheroid formation, and induced apoptosis by activation of caspase-3 and cleavage of poly-ADP ribose polymerase (PARP). NVP-LDE-225 induced expression of Bax and Bak, and inhibited the expression of Bcl-2, Bcl-XL, XIAP, cIAP1, cIAP2 and survivin. NVP-LDE-225 inhibited Gli transcriptional activity, Gli-DNA interaction and the expression of Gli1, Gli2, Patched1 and Patched-2 in prostate CSCs. Interestingly, NVP-LDE-225 induced PDCD4 and apoptosis and inhibited cell viability by suppressing miR-21. Furthermore, NVP-LDE-225 inhibited pluripotency-maintaining factors Nanog, Oct-4, c-Myc and Sox-2. The inhibition of Bmi-1 by NVP-LDE-225 was regulated by upregulation of miR-128. NVP-LDE-225 suppressed EMT by upregulating E-cadherin and inhibiting N-cadherin, Snail, Slug and Zeb1 by regulating the miR-200 family. Finally, NVP-LDE-225 inhibited CSC tumor growth, which was associated with the suppression of Gli1, Gli2, Patched-1, Patched-2, Cyclin D1, Bmi-1 and PCNA and cleavage of caspase-3 and PARP in tumor tissues derived from NOD/SCID IL2Rγ null mice. Overall, our findings suggest that inhibition of the Shh signaling pathway could therefore be a novel therapeutic option in treating prostate cancer.
Insights
Sonic hedgehog (Shh) pathway inhibition using NVP-LDE-225 suppresses prostate cancer stem cell (CSC) properties and tumor growth. This approach targets stemness, recurrence, and treatment resistance, offering a potential new therapy for prostate cancer management.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Stem Cell Research
Background:
- Prostate cancer stem cells (CSCs) drive tumor growth, recurrence, and treatment resistance.
- The Sonic hedgehog (Shh) signaling pathway is critical for stemness and tumorigenesis.
Purpose of the Study:
- To investigate how NVP-LDE-225 (a smoothened inhibitor) affects prostate CSCs' stem cell characteristics and tumor growth.
- To elucidate the molecular mechanisms underlying NVP-LDE-225's action on prostate cancer.
Main Methods:
- Assessed NVP-LDE-225 effects on CSC viability, sphere formation, apoptosis, and epithelial-mesenchymal transition (EMT) in vitro.
- Evaluated tumor growth inhibition and molecular changes in vivo using NOD/SCID IL2Rγ null mice.
- Analyzed Shh pathway components (Gli, Patched), stemness factors (Nanog, Oct-4), EMT markers, and apoptosis-related proteins.
Main Results:
- NVP-LDE-225 reduced CSC viability and sphere formation, induced apoptosis via caspase-3/PARP activation, and modulated Bcl-2 family proteins.
- Inhibition of Gli transcriptional activity and downstream targets (Gli1, Gli2, Patched1/2) was observed.
- NVP-LDE-225 suppressed pluripotency factors, EMT, and tumor growth in vivo, correlating with apoptosis markers.
Conclusions:
- NVP-LDE-225 effectively targets prostate CSCs by inhibiting the Shh pathway, stemness, and EMT.
- Suppression of CSCs and tumor growth by NVP-LDE-225 suggests its potential as a novel therapeutic strategy for prostate cancer.
- Targeting the Shh pathway offers a promising avenue for managing prostate cancer, addressing recurrence and treatment resistance.
