Review
Biochemistry & Molecular Biology
Jian Yi Chai, Vaisnevee Sugumar, Mohammed Abdullah Alshawsh, Won Fen Wong, Aditya Arya, Pei Pei Chong, Chung Yeng Looi
Summary: The Hedgehog (Hh)-glioma-associated oncogene homolog (GLI) signaling pathway is highly conserved in mammals and plays crucial roles in cancer initiation and progression. GLI transcription factors are regulated by both SMO-dependent and SMO-independent mechanisms, with dysregulation leading to tumorigenesis in various cancers. Understanding the complex interplay between GLI and signaling elements could inspire new therapeutic breakthroughs for Hh-GLI-dependent cancers.
Article
Biochemistry & Molecular Biology
Huanxian Wu, Lishun Zhang, Boyu Chen, Baofang Ou, Jiahuan Xu, Nannan Tian, Danni Yang, Yangcheng Ai, Qianqing Chen, Dongling Quan, Tingting Zhang, Lin Lv, Yuanxin Tian, Jiajie Zhang, Shaoyu Wu
Summary: B13 is an effective drug that inhibits the proliferation and metastasis of colorectal cancer cells, inducing cell cycle arrest and apoptosis. It has low toxicity and superior antitumor activity compared to Vismodegib. By binding to Smo protein, B13 inhibits the expression of downstream gene Gli1 and its localization in the nucleus, overcoming resistance caused by SmoD473H mutations.
BIOORGANIC CHEMISTRY
(2023)
Article
Cell Biology
Ping Shi, Jia Tian, Julianne C. Mallinger, Dahao Ling, Loic P. Deleyrolle, Jeremy C. Mcintyre, Tamara Caspary, Joshua J. Breunig, Matthew R. Sarkisian
Summary: This study found that increasing ARL13B expression in glioma cells can promote the accumulation of SMO and GLI2 in cilia, and this accumulation is resistant to SMO inhibitors. Furthermore, the increase in ARL13B also leads to changes in ciliary membrane characteristics and retrograde transport, which further promote SMO and GLI accumulation in glioma cells.
Article
Biochemistry & Molecular Biology
Corvin D. Arveseth, John T. Happ, Danielle S. Hedeen, Ju-Fen Zhu, Jacob L. Capener, Dana Klatt Shaw, Ishan Deshpande, Jiahao Liang, Jiewei Xu, Sara L. Stubben, Isaac B. Nelson, Madison F. Walker, Kouki Kawakami, Asuka Inoue, Nevan J. Krogan, David J. Grunwald, Ruth Huttenhain, Aashish Manglik, Benjamin R. Myers
Summary: The Hedgehog (Hh) pathway plays a crucial role in organ development, homeostasis, and regeneration, with dysfunction leading to various cancers. Research suggests that SMO activates GLI by binding and sequestering PKA, contradicting traditional GPCR signaling paradigms. This mechanism could have broader implications for GPCR- and PKA-containing cascades in biology.
Article
Chemistry, Medicinal
Fei Zhao, Yiran Wu, Fang Zhou, Dongxiang Xue, Simeng Zhao, Wanglong Lu, Xiaoyan Liu, Tao Hu, Yanli Qiu, Rongyan Li, Tangjie Gu, Yueming Xu, Fei Xu, Guisheng Zhong, Zhongxing Jiang, Suwen Zhao, Houchao Tao
Summary: This study investigates the activation mechanism of the smoothened receptor (SMO) and finds that active SMO has a rigid near assembly, while inactive SMO has a free far assembly and may be captured by cholesterol.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Ophthalmology
Jing-Yu Qu, Yu-Ting Xiao, Ying-Ying Zhang, Hua-Tao Xie, Ming-Chang Zhang
Summary: The Hedgehog signaling pathway plays an important role in regulating proliferation and differentiation of RMGECs, potentially offering a therapeutic approach for treating meibomian gland dysfunction (MGD).
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
(2021)
Review
Biochemistry & Molecular Biology
Ngoc Minh Nguyen, Jungsook Cho
Summary: This review discusses the importance of the Hedgehog (Hh) signaling pathway in cancer, the emergence of Hh pathway inhibitors, and the mechanisms of drug resistance. Additionally, strategies to overcome resistance are addressed.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Oncology
Wenjing Huang, Han Liu, Wenfu Tan, Juan Wang
Summary: ABT-737 is identified as a selective Hh inhibitor that suppresses Hh signals far downstream of Smo and inhibits both wild-type and drug-resistant mutant Smo. It also delays the growth of drug-refractory Hh-dependent MB xenografts.
Article
Biochemistry & Molecular Biology
Ana Maria Zarate, Christian Espinosa-Bustos, Simon Guerrero, Angelica Fierro, Felipe Oyarzun-Ampuero, Andrew F. G. Quest, Lucia Di Marcotullio, Elena Loricchio, Miriam Caimano, Andrea Calcaterra, Matias Gonzalez-Quiroz, Adam Aguirre, Jaime Melendez, Cristian O. Salas
Summary: A study designed and synthesized new SMO antagonists with compound 4s showing the most active inhibition of cell growth, selective cytotoxicity to cancer cells, and the ability to induce cell cycle arrest and apoptosis. In vivo, 4s strongly inhibited tumor relapse and metastasis of melanoma cells in mice, and in vitro, it was more effective than vismodegib in inducing apoptosis in human cancer cells as a SMO antagonist and apoptosis inducer.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Chemistry, Medicinal
Li Chen, Maolun Liu, Han Yang, Shan Ren, Qiang Sun, Hui Zhao, Tianqi Ming, Shun Tang, Qiu Tao, Sha Zeng, Xianli Meng, Haibo Xu
Summary: It has been discovered that ursolic acid (UA), a compound found in medicinal herbs, has potent effects against colorectal cancer (CRC) by inhibiting non-canonical Hedgehog signaling. This study investigated the influence of UA on non-canonical Hedgehog signaling in CRC, and found that UA inhibited cell proliferation, induced apoptosis, and down-regulated signaling proteins in CRC cells. Furthermore, UA also improved symptoms, inhibited tumor growth, and induced apoptosis in a CRC xenograft model.
PHYTOTHERAPY RESEARCH
(2022)
Article
Oncology
Raoul Tibes, Heidi E. Kosiorek, Amylou C. Dueck, Jeanne Palmer, Lisa Sproat, James Bogenberger, Shahrukh Hashmi, Ruben Mesa, William Hogan, Mark R. Litzow, Aref Al-Kali
Summary: In this study, the combination of azacitidine and Sonidegib showed efficacy in newly diagnosed AML/MDS patients, but had limited response in relapsed/refractory cases of myeloid neoplasms.
Article
Cell Biology
Sarah Findakly, Vikas Daggubati, Galo Garcia, Sydney A. LaStella, Abrar Choudhury, Cecilia Tran, Amy Li, Pakteema Tong, Jason Q. Garcia, Natasha Puri, Jeremy F. Reiter, Libin Xu, David R. Raleigh
Summary: Hedgehog signaling in vertebrates is transduced through ciliary-associated sterol and oxysterol lipids, with enzymes like DHCR7 being negatively regulated and removed from the ciliary microenvironment upon Hedgehog stimulation, while enzymes like CYP7A1 are positively regulated to promote Hedgehog signaling. These findings shed light on how ciliary lipids are regulated to transduce Hedgehog signals.
JOURNAL OF CELL BIOLOGY
(2021)
Article
Chemistry, Medicinal
Christopher Lawson, Thowaiba Babikr Ahmed Alta, Georgia Moschou, Vasiliki Skamnaki, Theodora G. A. Solovou, Caroline Topham, Joseph Hayes, Timothy J. Snape
Summary: Medulloblastoma is a highly aggressive and heterogeneous tumor that accounts for 15-20% of childhood brain tumors. In this study, potent in vitro anticancer activity against medulloblastoma cell lines was achieved using first-generation compounds, leading to the development of second-generation compounds with up to sixty times the activity, providing promising new leads for further research.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Cell Biology
Natalia Garcia, Ayman Al-Hendy, Edmund C. Baracat, Katia Candido Carvalho, Qiwei Yang
Summary: This study investigated the expression profile of Hedgehog pathway markers in uterine leiomyosarcoma (LMS) cells and the inhibitory effects of targeted drugs on LMS cell behavior. Inhibiting SMO, GLI, and DNMTs showed promising results in reducing LMS proliferation, migration, and invasion, suggesting potential therapeutic targets for this aggressive tumor. Blocking multiple components in the Hedgehog pathway exhibited potentiated effects on inhibiting LMS malignant features, warranting further investigation for clinical applications.
Article
Surgery
Ronan J. Kelly, Amir M. Ansari, Tomoharu Miyashita, Marianna Zahurak, Frank Lay, A. Karim Ahmed, Louis J. Born, Maryam K. Pezhouh, Kevan J. Salimian, Christopher Ng, Aerielle E. Matsangos, Anne-Heloise Stricker-Krongrad, Ken-ichi Mukaisho, Guy P. Marti, Christine H. Chung, Marcia I. Canto, Michelle A. Rudek, Stephen J. Meltzer, John W. Harmon
Summary: Itraconazole significantly reduces the development of esophageal adenocarcinoma and SHH expression in a preclinical animal model of Barrett's Metaplasia. In humans, BE tissue expresses higher levels of SHH, Indian Hedgehog, and bone morphogenic protein compared to normal squamous esophageal epithelium.
Review
Immunology
James M. Conley, Michael P. Gallagher, Leslie J. Berg
FRONTIERS IN IMMUNOLOGY
(2016)
Review
Immunology
Amy H. Andreotti, Raji E. Joseph, James M. Conley, Janet Iwasa, Leslie J. Berg
ANNUAL REVIEW OF IMMUNOLOGY, VOL 36
(2018)
Article
Chemistry, Medicinal
Martin R. Tremblay, Andre Lescarbeau, Michael J. Grogan, Eddy Tan, Grace Lin, Brian C. Austad, Lin-Chen Yu, Mark L. Behnke, Somarajan J. Nair, Margit Hagel, Kerry White, James Conley, Joseph D. Manna, Teresa M. Alvarez-Diez, Jennifer Hoyt, Caroline N. Woodward, Jens R. Sydor, Melissa Pink, John MacDougall, Matthew J. Campbell, Jill Cushing, Jeanne Ferguson, Michael S. Curtis, Karen McGovern, Margaret A. Read, Vito J. Palombella, Julian Adams, Alfredo C. Castro
JOURNAL OF MEDICINAL CHEMISTRY
(2009)
Article
Multidisciplinary Sciences
Ribhu Nayar, Elizabeth Schutten, Sonal Jangalwe, Philip A. Durost, Laurie L. Kenney, James M. Conley, Keith Daniels, Michael A. Brehm, Raymond M. Welsh, Leslie J. Berg
Editorial Material
Immunology
James M. Conley, Leslie J. Berg
Article
Immunology
James M. Conley, Michael P. Gallagher, Anjana Rao, Leslie J. Berg
JOURNAL OF IMMUNOLOGY
(2020)
Article
Multidisciplinary Sciences
Michael P. Gallagher, James M. Conley, Pranitha Vangala, Manuel Garber, Andrea Reboldi, Leslie J. Berg
Summary: The strength of peptide:MHC interactions with the T cell receptor (TCR) is correlated with key aspects of T cell activation, including cell division time and effector cell response scale. ITK plays a crucial role in orchestrating the optimal activation of separate TCR downstream pathways, particularly aiding NF-κB activation. Variations in TCR signal strength can produce patterns of graded gene expression in activated T cells, highlighting the complex interplay between signaling cascades in T cell activation programming.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)