Review
Biochemistry & Molecular Biology
Ian de Ridder, Martijn Kerkhofs, Santhini Pulikkal Veettil, Wim Dehaen, Geert Bultynck
Summary: The Bcl-2 family proteins play crucial roles in apoptosis regulation, with emerging potential in targeting the BH4 domain for cancer therapeutics. However, improved tools and on-target antagonizing small molecules are still necessary for effectively antagonizing the non-canonical functions of Bcl-2.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
(2021)
Article
Oncology
Yihua Lin, Yiling Zhao, Minggui Chen, Zishuo Li, Qiao Liu, Jian Chen, Yi Ding, Chunyong Ding, Ye Ding, Cuiling Qi, Lingyun Zheng, Jiangchao Li, Rongxin Zhang, Jia Zhou, Lijing Wang, Qian-Qian Zhang
Summary: In this study, a novel Bcl-2-BH4 antagonist CYD0281 was identified, which induced conformational changes of Bcl-2 to convert it into a pro-apoptotic molecule. CYD0281 exhibited significant anti-angiogenic effects both in vitro and in vivo, and inhibited breast cancer tumor growth. The findings suggest that CYD0281 plays a crucial role in anti-angiogenesis and may be developed as a potential anti-tumor drug candidate for breast cancer.
Article
Chemistry, Multidisciplinary
Jing-yi Zhou, Rui-rui Yang, Jie Chang, Jia Song, Zi-sheng Fan, Ying-hui Zhang, Cheng-hao Lu, Hua-liang Jiang, Ming-yue Zheng, Su-lin Zhang
Summary: This study describes the discovery and identification of a novel BCL-2 inhibitor, DC-B01, which targets the BH4 domain of BCL-2. The results indicate that DC-B01 induces cell apoptosis, inhibits tumor growth, and suppresses the transcriptional activity of c-Myc by disrupting the interaction between BCL-2 and c-Myc.
ACTA PHARMACOLOGICA SINICA
(2023)
Article
Oncology
Vishnupriya Kanakaveti, Sakthivel Ramasamy, Rahul Kanumuri, Vaishnavi Balasubramanian, Roshni Saravanan, Inemai Ezhil, Ravishankar Pitani, Ganesh Venkatraman, Suresh Kumar Rayala, M. Michael Gromiha
Summary: This study identified three novel BH4 mimetics that exhibit nanomolar activities against triple-negative breast cancer cells. These compounds induce apoptosis and have high specificity towards cancer cells. They show promising potential for clinical translation in targeting this challenging subtype of breast cancer.
Article
Biochemistry & Molecular Biology
Nicolas Rosa, Hristina Ivanova, Larry E. Wagner, Justin Kale, Rita La Rovere, Kirsten Welkenhuyzen, Nikolaos Louros, Spyridoula Karamanou, Victoria Shabardina, Irma Lemmens, Elien Vandermarliere, Kozo Hamada, Hideaki Ando, Frederic Rousseau, Joost Schymkowitz, Jan Tavernier, Katsuhiko Mikoshiba, Anastassios Economou, David W. Andrews, Jan B. Parys, David Yule, Geert Bultynck
Summary: The study shows that Bcl-xL and Bcl-2 have similar anti-apoptotic effects in controlling endoplasmic reticulum Ca2+ release, challenging the current understanding of their divergent functions in Ca2+ signaling modulation.
CELL DEATH AND DIFFERENTIATION
(2022)
Article
Multidisciplinary Sciences
Ling Chen, Qidong Cai, Rui Yang, Haiyan Wang, Huli Ling, Tiansheng Li, Na Liu, Zuli Wang, Jingyue Sun, Tania Tao, Ying Shi, Ya Cao, Xiang Wang, Desheng Xiao, Shuang Liu, Yongguang Tao
Summary: This study found that GINS4 is involved in the regulation of ferroptosis in lung adenocarcinoma (LUAD). CRISPR/Cas9-mediated GINS4 knockout promoted ferroptosis, especially in G(2)/M phase cells. The mechanism revealed that GINS4 suppressed p53 stability by activating Snail and inhibiting p53 acetylation, with p53 lysine residue 351 playing a key role in GINS4-suppressed p53-mediated ferroptosis. These findings suggest that GINS4 may be a potential oncogene and a therapeutic target for LUAD.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Review
Biochemistry & Molecular Biology
Deeksha Kaloni, Sarah T. Diepstraten, Andreas Strasser, Gemma L. Kelly
Summary: Acquired resistance to cell death is a key characteristic of cancer. The BCL-2 protein family members have important roles in regulating apoptotic cell death. Abnormal expression of pro-survival BCL-2 family proteins or reduction in pro-apoptotic BCL-2 family proteins, both leading to inhibition of apoptosis, are commonly observed in various types of cancer. The critical role of pro-survival and pro-apoptotic BCL-2 family proteins in apoptosis regulation makes them attractive targets for cancer treatment. This review discusses the roles of different pro-survival and pro-apoptotic members of the BCL-2 protein family in normal development and organismal function, as well as how defects in apoptosis control contribute to cancer development and therapy resistance. Lastly, the development of inhibitors targeting pro-survival BCL-2 proteins, known as BH3-mimetic drugs, as novel agents for cancer therapy is discussed.
Review
Pharmacology & Pharmacy
Alakananda Basu
Summary: The interplay between apoptosis and senescence is crucial in cancer development, and targeting the Bcl-2 family proteins could be a promising strategy for cancer therapy. Therapy-induced senescence (TIS), induced by chemotherapeutic agents, has been controversial in its effect on therapeutic outcome. Clearance of senescent cells and overcoming their pro-survival mechanisms are important challenges in cancer treatment. This review article discusses recent literature on the role of the Bcl-2 family proteins in apoptosis and senescence, and the progress and limitations in targeting them for cancer therapy.
PHARMACOLOGY & THERAPEUTICS
(2022)
Article
Chemistry, Physical
Liwen F. Wan, Tom Autrey, Brandon C. Wood
Summary: This study aims to understand the kinetic limitations of Mg(BH4)(2) through first-principles simulations. It identifies the rate-limiting step during BH4--B3H8- conversion and clarifies the existence of molecular species as intermediates in the Mg-BH4-Mg matrix. This provides valuable insights for the development of efficient hydrogen storage materials.
JOURNAL OF PHYSICAL CHEMISTRY LETTERS
(2022)
Review
Oncology
Shirin Hafezi, Mohamed Rahmani
Summary: Apoptosis is the main form of cell death regulated by the BCL-2 family of proteins. Overexpression of antiapoptotic proteins in malignant cells offers survival advantages but also presents opportunities for targeted therapies. Studies targeting BCL-2 proteins, including the development of venetoclax, show promise for effective treatment in cancer.
Review
Biochemistry & Molecular Biology
Linlin Zhang, Zaiming Lu, Xiangxuan Zhao
Summary: Apoptosis deficiency is a crucial feature in neoplastic diseases, with the Bcl-2 family of proteins playing a decisive role in regulating apoptosis. Studies have shown that hyperactivation of Bcl-2 anti-apoptotic effects is associated with cancer occurrence and resistance to therapy, making targeting Bcl-2 inactivation a promising route for cancer treatment.
BIOCHIMICA ET BIOPHYSICA ACTA-REVIEWS ON CANCER
(2021)
Review
Biochemistry & Molecular Biology
Geoffrey Brown
Summary: There is a need for agents to target cancer stem cells in order to effectively treat cancer and prevent relapse and metastasis, as conventional therapies often spare these cells. Targeting retinoic acid receptor (RAR)gamma is a promising approach, as it is selectively expressed in primitive cells and has been implicated in various human cancers. Antagonizing RAR gamma shows potential in inducing necroptosis in cancer stem cells.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Oncology
Manish Thiruvalluvan, Sandrine Billet, Neil A. Bhowmick
Summary: The study found that glutamine is a crucial nutrient in driving prostate cancer growth, and understanding its role in radiation sensitivity is important. By using the drug L-asparaginase, which reduces glutamine levels, it was found that cancer cells became more sensitive to radiation therapy.
Review
Oncology
Shanna Qian, Zhong Wei, Wanting Yang, Jinling Huang, Yinfeng Yang, Jinghui Wang
Summary: Apoptosis, a crucial biological process, plays a central role in cancer development and traditional cytotoxic therapies. The study of BCL-2 family proteins in regulating apoptosis and the development of anticancer drugs targeting BCL-2 anti-apoptotic proteins has gained increasing attention, showing great potential in cancer therapy.
FRONTIERS IN ONCOLOGY
(2022)
Article
Medicine, Research & Experimental
Chia-Hao Tung, Meng-Fan Huang, Chen-Hsien Liang, Yi-Ying Wu, Jia-En Wu, Cheng-Lung Hsu, Yuh-Ling Chen, Tse-Ming Hong
Summary: This study reveals that alpha-Catulin enhances cancer stemness in lung adenocarcinoma by inhibiting the degradation of KLF5 mediated by WWP1. The interaction between alpha-Catulin and integrin-linked kinase (ILK) disrupts the alpha-Catulin-KLF5 interaction, leading to the degradation of KLF5 and decreased cancer stemness driven by alpha-Catulin. Furthermore, a CTNNAL1/ILK/KLF5 three-gene signature is identified to predict poor overall survival in lung adenocarcinoma patients.
Editorial Material
Biochemistry & Molecular Biology
Jan B. Parys, Geert Bultynck
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
(2022)
Article
Biochemistry & Molecular Biology
Nicolas Rosa, Hristina Ivanova, Larry E. Wagner, Justin Kale, Rita La Rovere, Kirsten Welkenhuyzen, Nikolaos Louros, Spyridoula Karamanou, Victoria Shabardina, Irma Lemmens, Elien Vandermarliere, Kozo Hamada, Hideaki Ando, Frederic Rousseau, Joost Schymkowitz, Jan Tavernier, Katsuhiko Mikoshiba, Anastassios Economou, David W. Andrews, Jan B. Parys, David Yule, Geert Bultynck
Summary: The study shows that Bcl-xL and Bcl-2 have similar anti-apoptotic effects in controlling endoplasmic reticulum Ca2+ release, challenging the current understanding of their divergent functions in Ca2+ signaling modulation.
CELL DEATH AND DIFFERENTIATION
(2022)
Review
Cell Biology
Peter Vandenabeele, Geert Bultynck, Savvas N. Savvides
Summary: Regulated cell death (RCD) relies on the activation and recruitment of pore-forming proteins (PFPs) to execute specific cell death pathways. This review discusses the structural rearrangements incurred by RCD-related PFPs and describes the mechanisms behind the conversion from an autoinhibited state to a membrane-embedded state. It also highlights the formation and maturation of membrane pores and the implications of different cell death modalities on physiological and pathophysiological processes.
NATURE REVIEWS MOLECULAR CELL BIOLOGY
(2023)
Article
Multidisciplinary Sciences
Lara E. Terry, Vikas Arige, Julika Neumann, Amanda M. Wahl, Taylor R. Knebel, James W. Chaffer, Sundeep Malik, Adrian Liston, Stephanie Humblet-Baron, Geert Bultynck, David I. Yule
Summary: Mutations in IP(3)R3 were found to result in decreased receptor function, leading to elevated cytosolic Ca2+ levels, decreased endoplasmic reticulum Ca2+ store content, and constitutively open channels in the absence of stimulation. These mutations exhibited different levels of channel activity.
Editorial Material
Biochemistry & Molecular Biology
Geert Bultynck, Shazia Khan, M. Lienhard Schmitz
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
(2023)
Article
Cell Biology
Ian de Ridder, Martijn Kerkhofs, Fernanda O. Lemos, Jens Loncke, Geert Bultynck, Jan B. Parys
Summary: Endoplasmic reticulum (ER)-mitochondria contact sites are crucial for Ca2+ flux and involve multiple proteins. Inositol 1,4,5-trisphosphate receptors (IP3Rs) play a central role in tethering ER and mitochondria and transporting Ca2+. The IP3R-GRP75-VDAC1 complex acts as a hub for stabilizing and regulating Ca2+ transfer into mitochondria.
Article
Neurosciences
D. Chernyuk, M. Callens, M. Polozova, A. Gordeev, M. Chigriai, A. Rakovskaya, A. Ilina, E. Pchitskaya, C. Van den Haute, T. Vervliet, G. Bultynck, I. Bezprozvanny
Summary: Alzheimer's disease is the most common cause of dementia, and dysregulation of intracellular Ca2+ signaling is an early feature in the pathology. This study examined the hypothesis that expression of Bcl-2 proteins can normalize dysregulated Ca2+ signaling in a mouse model of AD and potentially prevent or slow the progression of the disease. The results indicate that Bcl-2 protein expression leads to synaptoprotective and amyloid-protective effects in the mouse model.
IBRO NEUROSCIENCE REPORTS
(2023)
Editorial Material
Cell Biology
Jan B. Parys, Geert Bultynck
Article
Cell Biology
Julius Ronkko, Yago Rodriguez, Tiina Rasila, Ruben Torregrosa-Munumer, Jana Pennonen, Jouni Kvist, Emilia Kuuluvainen, Ludo Van Den Bosch, Ville Hietakangas, Geert Bultynck, Henna Tyynismaa, Emil Ylikallio
Summary: Through the development of single and triple Inositol 1,4,5-trisphosphate receptors (IP3Rs) knockouts in human induced pluripotent stem cells (hiPSC), it was found that IP3Rs are not essential for hiPSC identity and pluripotency, but regulate mitochondrial metabolism. This set of knockout hiPSC is a valuable resource for investigating IP3Rs in human cell types of interest.
Article
Cell Biology
Flore Sneyers, Martijn Kerkhofs, Femke Speelman-Rooms, Kirsten Welkenhuyzen, Rita La Rovere, Ahmed Shemy, Arnout Voet, Guy Eelen, Mieke Dewerchin, Stephen W. G. Tait, Bart Ghesquiere, Martin D. Bootman, Geert Bultynck
Summary: Intracellular Ca2+ signals play a crucial role in various cellular processes. Research has shown that BAPTAi can induce apoptosis in cancer cells by inhibiting mTORC1 activity and impairing glycolysis, independent of Ca2+ signaling. Additionally, direct inhibition of PFKFB3 emerges as a potential therapeutic target in MCL-1-dependent cancers.
CELL DEATH & DISEASE
(2023)
Article
Cell Biology
Elzbieta Kania, Jaclyn S. Long, David G. McEwan, Kirsten Welkenhuyzen, Rita La Rovere, Tomas Luyten, John Halpin, Evy Lobbestael, Veerle Baekelandt, Geert Bultynck, Kevin M. Ryan, Jan B. Parys
Summary: Mutations in the LRRK2 gene are the most common genetic cause of Parkinson's disease, and they also have importance in Crohn's disease and cancer. A study found that the phosphorylation status of LRRK2 affects its function, and the S910/S935/S955/S973 phosphorylation sites play a crucial role in regulating LRRK2-mediated autophagy. Cells with quadruple LRRK2 phosphomutations showed impaired autophagy during starvation, while treatment with LRRK2 kinase inhibitors did not affect autophagy. Increased LRRK2 kinase activity was found to drive autophagy impairment through phosphorylation of downstream targets Rab8a and Rab10.
CELL DEATH & DISEASE
(2023)
Article
Cell Biology
Fernanda O. Lemos, Ian de Ridder, Martin D. Bootman, Geert Bultynck, Jan B. Parys
Summary: PKM2 regulates calcium handling in the cytosol and mitochondria separately, while TAT-D5SD induces apoptosis by disrupting the PKM2:IP3R interaction.
Article
Medicine, Research & Experimental
Luc Leybaert, Maarten A. J. De Smet, Alessio Lissoni, Rosalie Allewaert, H. Llewelyn Roderick, Geert Bultynck, Mario Delmar, Karin R. Sipido, Katja Witschas
Summary: This paragraph mainly discusses the role of connexins in cardiac function. Connexins form hemichannels and gap junctions, and gap junctions are responsible for transmitting electrical and chemical signals between myocardial cells and specialized conduction system cells to synchronize the cardiac cycle and control cardiac pump function. Under pathological conditions, gap junctions close and hemichannels open, leading to disruption of cardiac function and homeostasis. Current evidence shows that hemichannels play an emerging role in myocardial ischemia and arrhythmia, and there are now tools available to selectively inhibit hemichannels without inhibiting gap junctions, as well as to stimulate the incorporation of hemichannels into gap junctions. We review experimental evidence for the contribution of hemichannels to pro-arrhythmic events in ventricular and atrial cardiomyocytes, and link these findings to the molecular control of connexin-43-based hemichannel opening. We conclude that a double-edged approach of both preventing hemichannel opening and preserving gap junctional function will be crucial for further research and development of new connexin-based experimental approaches for treating heart disease.
JOURNAL OF CLINICAL INVESTIGATION
(2023)
Article
Immunology
Julika Neumann, Erika Van Nieuwenhove, Lara E. Terry, Frederik Staels, Taylor R. Knebel, Kirsten Welkenhuyzen, Kourosh Ahmadzadeh, Mariah R. Baker, Margaux Gerbaux, Mathijs Willemsen, John S. Barber, Irina I. Serysheva, Liesbeth De Waele, Francois Vermeulen, Susan Schlenner, Isabelle Meyts, David Yule, Geert Bultynck, Rik Schrijvers, Stephanie Humblet-Baron, Adrian Liston
Summary: Calcium signaling is crucial for lymphocyte activation, and disruptions of store-operated calcium entry can lead to severe immunodeficiency. In this study, genetic variations of the ITPR3 gene were identified in two Caucasian patients with immunodeficiency, indicating a potential link between these variations and impaired immune responses. The findings demonstrate the functional connection between defective endoplasmic reticulum calcium channels and immunodeficiency, highlighting the importance of IP(3)Rs as diagnostic targets for patients with specific inborn errors of immunity.
CELLULAR & MOLECULAR IMMUNOLOGY
(2023)
Correction
Immunology
Julika Neumann, Erika Van Nieuwenhove, Lara E. Terry, Frederik Staels, Taylor R. Knebel, Kirsten Welkenhuyzen, Kourosh Ahmadzadeh, Mariah R. Baker, Margaux Gerbaux, Mathijs Willemsen, John S. Barber, Irina I. Serysheva, Liesbeth De Waele, Francois Vermeulen, Susan Schlenner, Isabelle Meyts, David I. Yule, Geert Bultynck, Rik Schrijvers, Stephanie Humblet-Baron, Adrian Liston
CELLULAR & MOLECULAR IMMUNOLOGY
(2023)