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Prostaglandin E1 Inhibits GLI2 Amplification-Associated Activation of the Hedgehog Pathway and Drug Refractory Tumor Growth

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Prostaglandin E1 Inhibits GLI2 Amplification-Associated Activation of the Hedgehog Pathway and Drug Refractory Tumor Growth Author Manuscript Published OnlineFirst on May 5, 2020; DOI: 10.1158/0008-5472.CAN-19-2052 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Prostaglandin E1 Inhibits GLI2 Amplification-Associated 2 Activation of the Hedgehog Pathway and Drug Refractory 3 Tumor Growth 4 Fujia Wu1,2, Chenze Zhang1,2, Chen Zhao1, Hao Wu1,2, Zhaoqian Teng1,2,3, Tao Jiang4,5,6 *, 5 Yu Wang1,2,3 * 6 1. State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, 7 Chinese Academy of Sciences, Beijing 100101, China 8 2. University of Chinese Academy of Sciences, Beijing 100049, China 9 3. Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, 10 China 11 4. Department of Neurosurgery, Beijing TianTan Hospital, Capital Medical University, 12 Beijing 100050, China 13 5. Beijing Neurosurgical Institute, Capital Medical University, Beijing 100050, China 14 6. China National Clinical Research Center for Neurological Diseases, Beijing 100070, 15 China 16 * Corresponding Authors: Yu Wang, State Key Laboratory of Stem Cell and Reproductive 17 Biology, Institute of Zoology, Chinese Academy of Sciences, 1 Beichen West Road, Beijing 18 100101, China. Phone: +86-10-82619461; E-mail: [email protected]; and Tao Jiang, 19 Department of Neurosurgery, Beijing TianTan Hospital, Capital Medical University, Beijing 20 100050, China. Phone: +86-10-59975049; E-mail: [email protected] 21 Current address for Yu Wang: College of Life Sciences and Oceanography, Shenzhen 22 University, Shenzhen, China. 23 Running title: PGE1 inhibits GLI2 activity and drug refractory tumor growth. 24 Conflict of interest statement: The authors declare no potential conflicts of interest. 25 Page 1 of 29 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on May 5, 2020; DOI: 10.1158/0008-5472.CAN-19-2052 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Abstract 2 Aberrant activation of the Hedgehog (HH) signaling pathway underlines the initiation and 3 progression of a multitude of cancers. The effectiveness of the leading drugs vismodegib 4 (GDC-0449) and sonidegib (LDE225), both Smoothened (SMO) antagonists, is compromised 5 by acquisition of mutations that alter pathway components, notably secondary mutations in 6 SMO and amplification of GLI2, a transcriptional mediator at the end of the pathway. 7 Pharmacological blockade of GLI2 activity could ultimately overcome these diversified 8 refractory mechanisms, which would also be effective in a broader spectrum of primary 9 tumors than current SMO antagonists. To this end, we conducted a high-content screen 10 directly analyzing the ciliary translocation of GLI2, a key event for GLI2 activation in HH 11 signal transduction. Several prostaglandin compounds were shown to inhibit accumulation of 12 GLI2 within the primary cilium (PC). In particular, prostaglandin E1 (PGE1), an 13 FDA-approved drug, is a potent GLI2 antagonist that overcame resistance mechanisms of 14 both SMO mutagenesis and GLI2 amplification. Consistent with a role in HH pathway 15 regulation, EP4 receptor localized to the PC. Mechanistically, PGE1 inhibited HH signaling 16 through the EP4 receptor, enhancing cAMP-PKA activity, which promoted phosphorylation 17 and degradation of GLI2 via the ubiquitination pathway. PGE1 also effectively inhibited the 18 growth of drug refractory human medulloblastoma (MB) xenografts. Together, these results 19 identify PGE1 and other prostaglandins as potential templates for complementary therapeutic 20 development to circumvent resistance to current generation SMO antagonists in use in the 21 clinic. 22 Significance 23 Findings show that PGE1 exhibits pan-inhibition against multiple drug refractory activities 24 for Hedgehog-targeted therapies and elicits significant anti-tumor effects in xenograft models 25 of drug refractory human medulloblastoma mimicking GLI2 amplification. 26 Page 2 of 29 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on May 5, 2020; DOI: 10.1158/0008-5472.CAN-19-2052 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Introduction 2 The evolutionarily conserved HH signaling pathway plays critical roles in embryonic 3 patterning and adult tissue homeostasis (1,2). Hyperactive HH signaling has been linked to a 4 range of malignant tumors through tumor initiation, maintenance of tumor stem/progenitor 5 cells, and support of tumor-stroma interaction (3,4). Therefore, the HH signaling has emerged 6 as a therapeutic target of interest for cancer therapy and intensive efforts have been made to 7 develop targeted pathway antagonists. 8 Mammalian HH signal transduction is controlled by the Patched1 (PTCH1)-mediated 9 suppression of SMO, a seven-pass transmembrane protein which traffics continuously 10 through the primary cilium (PC) (5,6). Inactive SMO failed to regulate the activity state of 11 GLI2, the primary transcription activator of HH pathway, which thus was sequentially 12 phosphorylated by protein kinase A (PKA), glycogen synthase kinase-3β (GSK-3β), and 13 casein kinase 1 (CK1), and trafficked to the proteasome for degradation. On HH ligand (Sonic 14 hedgehog [SHH], Desert hedgehog [DHH], or Indian hedgehog [IHH]) binding to the shared 15 receptor PTCH1, the inhibitory effect on SMO is relieved, enabling SMO ciliary 16 accumulation and activation (5,6). Consequently, GLI2 translocates in activated full-length 17 form from the cilium to the nucleus (7), where it induces orchestrated expression of target 18 genes, including GLI1 and PTCH1. 19 Constitutive HH signaling contributes to tumorigenesis mainly through two types of 20 mechanisms. First, ligand-independent hyperactive pathway activity within the tumor cell 21 drives tumorigenesis in basal cell carcinoma (BCC), the most common cancer in Caucasian 22 population (8), medulloblastoma (MB), the most common childhood brain cancer (9), and 23 rhabdomyosarcoma (RMS) (10). Almost all BCC is initiated by ligand-independent HH 24 activity, most commonly through PTCH1 loss-of-function or SMO gain-of-function mutations 25 (11,12). Similarly, hyperactive HH signaling has emerged as the driver in approximately 30% 26 of MB through ligand-independent mechanisms including inactivating mutations in PTCH1 27 and SUFU, and genomic amplification of GLI2 (13-15). Second, HH pathway activation in 28 surrounding stromal cells has been found to support the growth of tumor cells in a paracrine 29 manner, whereby stromal cells receive HH ligand from tumor cells and secret stimulatory Page 3 of 29 Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on May 5, 2020; DOI: 10.1158/0008-5472.CAN-19-2052 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 factor in response for tumor progression (16). Such mechanism was documented in a broad 2 range of malignancies, most notably those in blood, pancreas, lung, stomach, colon, and 3 prostate (3). Clinical implications of the paracrine mechanism of action are yet to be clarified 4 as most clinical trials using HH pathway antagonists to treat these cancers did not meet a 5 positive conclusion (4). However, glasdegib was recently approved by the U.S. Food and 6 Drug Administration (FDA) for acute myeloid leukemia (AML), thus highlighting potential 7 expanded use of HH targeted cancer therapy beyond BCC and MB (17). 8 Cyclopamine, a natural compound found in wild corn lily (Veratrum californicum), was 9 identified as the first HH pathway inhibitor directly targeting SMO (18). Since then, many 10 more SMO inhibitors have been developed and several of them, including vismodegib, 11 sonidegib, glasdegib, LY2940680, and BMS-833923, have delivered promising results in 12 preclinical and clinical studies in HH-dependent cancers (3). Both vismodegib and sonidegib 13 have been approved by the U.S. FDA for treatment of advanced BCC (19,20). However, 14 acquired resistance to vismodegib and sonidegib limits their long-term efficacy. Drug 15 resistance can be acquired by genetic aberrations of multiple pathway components including 16 SMO mutations, SUFU mutations, and GLI2 amplifications (21-24). Notably, intra-tumor 17 heterogeneity of those drug refractory mechanisms was identified, further complicating the 18 situation that next generation cancer therapy needs to tackle (21). In addition, current 19 anti-SMO therapies failed to target primary tumors harboring mutations downstream of SMO 20 level (25). 21 The emergence of multiple drug resistance mechanisms associated with current SMO 22 antagonists and lack of therapies targeting HH pathway downstream of SMO level has 23 prompted our investigations into alternative approaches. From a perspective of pathway 24 epistasis, we reasoned that targeting hyperactive GLI2, the central transcription activator of 25 the pathway, would potentially deliver more effective therapeutic interventions that may 26 pan-inhibit various drug refractory mechanisms. Herein, we reported the discovery of a 27 number of prostaglandins in a high content screening for small molecules inhibiting GLI2 28 ciliary accumulation. We demonstrated that prostaglandin
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