Drugging the Cancer Stem Cell Compartment: Lessons Learned from the Hedgehog and Wnt Signal Transduction Pathways

Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, 75390, USA.
Annual Review of Pharmacology (Impact Factor: 18.37). 01/2010; 51(1):289-310. DOI: 10.1146/annurev-pharmtox-010510-100558
Source: PubMed


Cell-cell communication mediated by the secreted Hedgehog (Hh) and Wnt signaling molecules is essential to the coordination of cell fate decision making throughout the metazoan lifespan. From decades of genetically based interrogation, core components constituting the Hh and Wnt signal transduction pathways have been assembled, and a deep appreciation of how these signals elaborate distinct bodily tissues during development has been established. On the other hand, our incapacity to leverage similar genetic approaches to study adult organ systems has limited our understanding of how these molecules promote tissue renewal and regeneration through stem cell regulation. We discuss recent progress in the use of chemically based approaches to achieve control of these pathway activities in a broad range of biological studies and therapeutic contexts. In particular, we discuss the unique experimental opportunities that chemical modulators of these pathways afford in exploring the cancer stem cell hypothesis.

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    • "We also examined if Gli-I and pemetrexed might show synergistic effects. Gli activation has been suggested to maintain the stem cell population, which contributes to drug resistance and recurrence [34]. Therefore, it is possible that Gli-inhibition might improve the effectiveness of pemetrexed. "
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    ABSTRACT: Malignant pleural mesothelioma (MPM) is a highly aggressive tumor with poor prognosis. Current treatment is rarely curative, thus novel meaningful therapies are urgently needed. Inhibition of Hedgehog (Hh) signaling at the cell membrane level in several cancers has shown anti-cancer activity in recent clinical studies. Evidence of Hh-independent Gli activation suggests Gli as a more potent therapeutic target. The current study is aimed to evaluate the potential of Gli as a therapeutic target to treat MPM. The expression profiles of Gli factors and other Hh signaling components were characterized in 46 MPM patient tissue samples by RT-PCR and immunohistochemistry. Cultured cell lines were employed to investigate the requirement of Gli activation in tumor cell growth by inhibiting Gli through siRNA or a novel small molecule Gli inhibitor (Gli-I). A xenograft model was used to evaluate Gli-I in vivo. In addition, a side by side comparison between Gli and Smoothened (Smo) inhibition was conducted in vitro using siRNA and small molecule inhibitors. Our study reported aberrant Gli1 and Gli2 activation in a large majority of tissues. Inhibition of Gli by siRNAs or Gli-I suppressed cell growth dramatically both in vitro and in vivo. Inhibition of Gli exhibited better cytotoxicity than that of Smo by siRNA and small molecule inhibitors vismodegib and cyclopamine. Combination of Gli-I and pemetrexed, as well as Gli-I and vismodegib demonstrated synergistic effects in suppression of MPM proliferation in vitro. In summary, Gli activation plays a critical role in MPM. Inhibition of Gli function holds strong potential to become a novel, clinically effective approach to treat MPM.
    PLoS ONE 03/2013; 8(3):e57346. DOI:10.1371/journal.pone.0057346 · 3.23 Impact Factor
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    • "However, the identification of proliferation and differentiation pathways that are active in CSCs but not in normal, differentiated cells may offer unique opportunities for selective therapies (Dodge & Lum, 2011). Therefore, the discovery of prostate CSCs may offer a great opportunity to develop novel therapeutics targeting prostate CSCs to treat PCa. "
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    ABSTRACT: Prostate cancer is the most common malignant neoplasm in men and the second most frequent cause of cancer death for males in the United States. Recently, emerging evidence suggests that prostate cancer stem cells (CSCs) may play a critical role in the development and progression of prostate cancer. Therefore, targeting prostate CSCs for the prevention of tumor progression and treatment of prostate cancer could become a novel strategy for better treatment of patients diagnosed with prostate cancer. In this review article, we will summarize the most recent advances in the prostate CSCs field, with particular emphasis on targeting prostate CSCs to treat prostate cancer.
    Discovery medicine 02/2012; 13(69):135-42. · 3.63 Impact Factor
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    • "The study did not describe the membrane distribution of cholesterylated Shh; however this promising technique could allow for similar studies to examine the importance of cholesterol for directing Shh localization. Wnt and Hh are attractive targets for the development of anticancer therapeutics [28] [29]. Recent reports show that inhibition of Wnt3a palmitoylation by targeting the acyltransferase activity of Porcupine may be a viable strategy to counteract aberrant Wnt signaling [25]. "
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    ABSTRACT: Palmitoylation of the Wnt and Hedgehog proteins is critical for maintaining their physiological functions. To date, there are no reported studies that characterize the cellular distribution of the palmitoylated forms of these proteins. Here, we describe the subcellular localization of palmitoylated Wnt and Sonic Hedgehog by using a highly sensitive and non-radioactive labeling method that utilizes alkynyl palmitic acid. We show that palmitoylated Wnt and Sonic Hedgehog localize to cellular membrane fractions only, highlighting a role for palmitoylation in the membrane association of these proteins. The method described herein has the utility to validate inhibitors of Wnt and Hedgehog acyltransferases in drug discovery, and enables further investigations of the role of palmitoylation in the secretion and signaling of these proteins.
    FEBS letters 08/2011; 585(15):2501-6. DOI:10.1016/j.febslet.2011.06.033 · 3.17 Impact Factor
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