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.
Highlights
The sonic hedgehog (Shh) signaling pathway has a major role in prostate cancer progression, and abnormal Shh signaling has been implicated in the tumorigenesis of prostate tumors.[1]The normal function of the Shh ligand in the Shh pathway is to serve as a morphogen, inducing proper differentiation in embryogenesis.[2,3,4] Genomic alterations of the Shh pathway have been shown to lead to the development of prostate cancer.[5]Aberrant activation of the Shh pathway leads to an increase in cell survival and metastasis in cancer cells
We examined the effects of NVP-LDE-225 on cleavage of caspase-3 and poly-ADP ribose polymerase (PARP), which are the hallmarks of apoptosis
As NVP-LDE-225 inhibited cell viability and induced apoptosis in suggest the functional involvement of Bmi-1 in prostate cancer prostate cancer stem cells (CSCs), we examined the effect of NVP-LDE-225 on progression and maintenance
Summary
Aberrant activation of the Shh pathway leads to an increase in cell survival and metastasis in cancer cells. Such aberrant activity includes inactivating mutations of Ptch[1] or Sufu as well as activating mutations of Smo.[6,7,8] The binding of the Shh ligand to its receptor, Patched, transmits the signal to activate Gli[1] and Gli2.5,9 Abnormal regulation of the Gli family of genes had been shown to lead to tumorigenesis. It has been shown that expression of Gli[2] in certain types of cancer cells leads to increased invasiveness and metastatic capabilities of those cells.[10]
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