Dev Karan, Seema Dubey, Sumedha Gunewardena, Kenneth A Iczkowski, Manohar Singh, Pengyuan Liu, Angelo Poletti, Yeun-Mun Choo, Hui-Zi Chen, Mark T Hamann
The androgen receptor (AR) is the main driver in the development of castration-resistant prostate cancer, where the emergence of AR splice variants leads to treatment-resistant disease. Through detailed molecular studies of the marine alkaloid manzamine A (MA), we identified transcription factor E2F8 as a previously unknown regulator of AR transcription that prevents AR synthesis in prostate cancer cells. MA significantly inhibited the growth of various prostate cancer cell lines and was highly effective in inhibiting xenograft tumor growth in mice without any pathophysiological perturbations in major organs...
April 11, 2024: Molecular Oncology
Yonghwan Shin, Sungmin Kim, Gangning Liang, Woojin An
Matrix metalloproteinase 9 (MMP-9) is a member of the MMP family and has been recently identified as a nuclear protease capable of clipping histone H3 N-terminal tails (H3NT). This MMP-9-dependent H3NT proteolysis is critical for establishing an active state of gene transcription during osteoclast differentiation and melanoma development. However, whether H3NT cleavage by MMP-9 plays a similar role in other cellular events has not been explored. Here, we dissect the functional contribution of MMP-9-dependent H3NT clipping to colonic tumorigenesis by using a combination of genome-wide transcriptome data, ChIP/ChIPac-qPCR, CRISPR/dCas9 gene-targeting system, and in vivo xenograft models...
April 10, 2024: Molecular Oncology
Shohei Yoshida, Daisuke Kajiwara, Masanao Seki, Manabu Tayama, Yuki Tanaka, Hiroya Mizutani, Ryoto Fujita, Keisuke Yamamura, Shigeo Okajima, Masanori Asai, Kazuhisa Minamiguchi
Second-generation androgen receptor (AR) signaling inhibitors (ARSIs), such as abiraterone and enzalutamide, prolong the life of patients with castration-resistant prostate cancer (CRPC). However, patients receiving ARSIs ultimately develop resistance through various complex mechanisms, including AR mutations, constitutively active AR-splice variants (AR-Vs), and AR overexpression. Here, we characterized a novel AR pure antagonist, TAS3681, which inhibits AR transcriptional activity and downregulates AR-full length (AR-FL) and AR-Vs...
April 10, 2024: Molecular Oncology
Fatma Isil Yapici, Christina M Bebber, Silvia von Karstedt
Ferroptosis is a newly identified iron-dependent type of regulated cell death that can also be regarded as death caused by the specific collapse of the lipid antioxidant defence machinery. Ferroptosis has gained increasing attention as a potential therapeutic strategy for therapy-resistant cancer types. However, many ferroptosis-inducing small molecules do not reach the pharmacokinetic requirements for their effective clinical use yet. Nevertheless, their clinical optimization is under development. In this review, we summarize the current understanding of molecular pathways regulating ferroptosis, how cells protect themselves from the induction of ferroptotic cell death, and how a better understanding of cancer cell metabolism can represent vulnerabilities for ferroptosis-based therapies...
April 8, 2024: Molecular Oncology
Christopher E Grant, Amy L Flis, Leila Toulabi, Adriana Zingone, Emily Rossi, Krist Aploks, Heather Sheppard, Bríd M Ryan
Dopamine (DA) acts in various key neurological and physiological processes as both a neurotransmitter and circulating hormone. Over the past several decades, the DA signaling network has been shown to regulate the progression of several types of solid tumors, and considerable evidence has shown it is a druggable pathway in the cancer cell context. However, the specific activity and effect of these pathway components appears to be tissue-type and cell-context-dependent. In the present study, expression and methylation of dopamine receptor D1 (DRD1) were measured using RNA sequencing (RNAseq) and reverse transcription polymerase chain reaction (RT-PCR) in non-small cell lung cancer (NSCLC) samples, and validated using publicly available datasets, including The Cancer Genome Atlas (TCGA)...
April 4, 2024: Molecular Oncology
Matthias Schneider, Anna-Laura Potthoff, Georg Karpel-Massler, Patrick Schuss, Markus D Siegelin, Klaus-Michael Debatin, Hugues Duffau, Hartmut Vatter, Ulrich Herrlinger, Mike-Andrew Westhoff
In recent years, the discovery of functional and communicative cellular tumour networks has led to a new understanding of malignant primary brain tumours. In this review, the authors shed light on the diverse nature of cell-to-cell connections in brain tumours and propose an innovative treatment approach to address the detrimental connectivity of these networks. The proposed therapeutic outlook revolves around three main strategies: (a) supramarginal resection removing a substantial portion of the communicating tumour cell front far beyond the gadolinium-enhancing tumour mass, (b) morphological isolation at the single cell level disrupting structural cell-to-cell contacts facilitated by elongated cellular membrane protrusions known as tumour microtubes (TMs), and (c) functional isolation at the single cell level blocking TM-mediated intercellular cytosolic exchange and inhibiting neuronal excitatory input into the malignant network...
April 3, 2024: Molecular Oncology
Céleste Van Der Schueren, Philippe Decruyenaere, Francisco Avila Cobos, Johanna Bult, Jill Deleu, Laudonia Lidia Dipalo, Hetty Hilde Helsmoortel, Eva Hulstaert, Annelien Morlion, Elena Ramos Varas, Kathleen Schoofs, Wim Trypsteen, Eveline Vanden Eynde, Hanne Van Droogenbroeck, Kimberly Verniers, Jo Vandesompele, Anneleen Decock
Extracellular RNA (cell-free RNA; exRNA) from blood-derived liquid biopsies is an appealing, minimally invasive source of disease biomarkers. As pre-analytical variables strongly influence exRNA measurements, their reporting is essential for meaningful interpretation and replication of results. The aim of this review was to chart to what extent pre-analytical variables are documented, to pinpoint shortcomings and to improve future reporting. In total, 200 blood plasma exRNA studies published in 2018 or 2023 were reviewed for annotation of 22 variables associated with blood collection, plasma preparation, and RNA purification...
April 2, 2024: Molecular Oncology
Guochao Zhao, Ruijingfang Jiang, Ying Shi, Suizhi Gao, Dansong Wang, Zhilong Li, Yuhong Zhou, Jianlong Sun, Wenchuan Wu, Jiaxi Peng, Tiantao Kuang, Yefei Rong, Jie Yuan, Shida Zhu, Gang Jin, Yuying Wang, Wenhui Lou
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with a 5-year survival rate of 7.2% in China. However, effective approaches for diagnosis of PDAC are limited. Tumor-originating genomic and epigenomic aberration in circulating free DNA (cfDNA) have potential as liquid biopsy biomarkers for cancer diagnosis. Our study aims to assess the feasibility of cfDNA-based liquid biopsy assay for PDAC diagnosis. In this study, we performed parallel genomic and epigenomic profiling of plasma cfDNA from Chinese PDAC patients and healthy individuals...
April 1, 2024: Molecular Oncology
Marc Garcia-Moure, Andrew G Gillard, Marta M Alonso, Juan Fueyo, Candelaria Gomez-Manzano
Oncolytic viruses (OVs) are biological therapeutic agents that selectively destroy cancer cells while sparing normal healthy cells. Besides direct oncolysis, OV infection induces a proinflammatory shift in the tumor microenvironment and the release of tumor-associated antigens (TAAs) that might induce an anti-tumor immunity. Due to their immunostimulatory effect, OVs have been explored for cancer vaccination against specific TAAs. However, this approach usually requires genetic modification of the virus and the production of a new viral vector for each target, which is difficult to implement for low prevalent antigens...
April 1, 2024: Molecular Oncology
Akshatha N Srinivas, Diwakar Suresh, Prashant M Vishwanath, Suchitha Satish, Prasanna K Santhekadur, Saisudha Koka, Divya P Kumar
Metabolic dysfunction-associated steatohepatitis-driven hepatocellular carcinoma (MASH-HCC) is a global clinical challenge for which there is a limited understanding of disease pathogenesis and a subsequent lack of therapeutic interventions. We previously identified that tumor necrosis factor-alpha (TNF-α) upregulated apoptosis antagonizing transcription factor (AATF) in MASH. Here, we investigated the effect of TNF-α converting enzyme (TACE) inhibition as a promising targeted therapy against AATF-mediated steatohepatitis to hepatocarcinogenesis...
April 1, 2024: Molecular Oncology
Petra Marttila, Nadilly Bonagas, Christina Chalkiadaki, Hannah Stigsdotter, Korbinian Schelzig, Jianyu Shen, Crystal M Farhat, Amber Hondema, Julian Albers, Elisée Wiita, Azita Rasti, Ulrika Warpman Berglund, Ana Slipicevic, Oliver Mortusewicz, Thomas Helleday
The one-carbon metabolism enzyme bifunctional methylenetetrahydrofolate dehydrogenase/cyclohydrolase 2 (MTHFD2) is among the most overexpressed proteins across tumors and is widely recognized as a promising anticancer target. While MTHFD2 is mainly described as a mitochondrial protein, a new nuclear function is emerging. Here, we observe that nuclear MTHFD2 protein levels and association with chromatin increase following ionizing radiation (IR) in an ataxia telangiectasia mutated (ATM)- and DNA-dependent protein kinase (DNA-PK)-dependent manner...
March 27, 2024: Molecular Oncology
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March 23, 2024: Molecular Oncology
Anita G Kansy, Ramy Ashry, Al-Hassan M Mustafa, Abdallah M Alfayomy, Markus P Radsak, Yanira Zeyn, Matthias Bros, Wolfgang Sippl, Oliver H Krämer
Mammalian cells replicate ~ 3 × 109 base pairs per cell cycle. One of the key molecules that slows down the cell cycle and prevents excessive DNA damage upon DNA replication stress is the checkpoint kinase ataxia-telangiectasia-and-RAD3-related (ATR). Proteolysis-targeting-chimeras (PROTACs) are an innovative pharmacological invention to molecularly dissect, biologically understand, and therapeutically assess catalytic and non-catalytic functions of enzymes. This work defines the first-in-class ATR PROTAC, Abd110/Ramotac-1...
March 22, 2024: Molecular Oncology
Asma Ahmed, Stephen W G Tait
Mitochondrial metabolism and electron transport chain (ETC) function are essential for tumour proliferation and metastasis. However, the impact of ETC function on cancer immunogenicity is not well understood. In a recent study, Mangalhara et al. found that inhibition of complex II leads to enhanced tumour immunogenicity, T-cell-mediated cytotoxicity and inhibition of tumour growth. Surprisingly, this antitumour effect is mediated by succinate accumulation affecting histone methylation. Histone methylation promotes the transcriptional upregulation of major histocompatibility complex-antigen processing and presentation (MHC-APP) genes in a manner independent of interferon signalling...
March 22, 2024: Molecular Oncology
Bo Franzén, Gert Auer, Rolf Lewensohn
Precision cancer medicine (PCM) to support the treatment of solid tumors requires minimally invasive diagnostics. Here, we describe the development of fine-needle aspiration biopsy-based (FNA) molecular cytology which will be increasingly important in diagnostics and adaptive treatment. We provide support for FNA-based molecular cytology having a significant potential to replace core needle biopsy (CNB) as a patient-friendly potent technique for tumor sampling for various tumor types. This is not only because CNB is a more traumatic procedure and may be associated with more complications compared to FNA-based sampling, but also due to the recently developed molecular methods used with FNA...
March 22, 2024: Molecular Oncology
Alvaro Macias-Diaz, Jose J Lopez, Maria Bravo, Isaac Jardín, Waldo Luis Garcia-Jimenez, Francisco J Blanco-Blanco, Rosario Cerrato, Juan A Rosado
Store-operated Ca2+ entry (SOCE) is a major mechanism for Ca2+ influx in colorectal cancer (CRC) cells. This mechanism, regulated by the filling state of the intracellular Ca2+ stores, is mediated by the endoplasmic reticulum Ca2+ sensors of the stromal interaction molecules (STIM) family [stromal interaction molecule 1 (STIM1) and STIM2] and the Ca2+ -release-activated Ca2+ channels constituted by Orai family members, with predominance of calcium release-activated calcium channel protein 1 (Orai1). CRC cells exhibit enhanced SOCE due to remodeling of the expression of the key SOCE molecular components...
March 21, 2024: Molecular Oncology
Jeon Yeob Jang, Bok-Soon Lee, Mei Huang, Chorong Seo, Ji-Hye Choi, Yoo Seob Shin, Hyun Goo Woo, Chul-Ho Kim
Immune checkpoint blockers (ICBs) targeting programmed cell death protein 1 (PD-1) have been proven to be an effective first-line therapy against programmed cell death 1 ligand 1 (PD-L1; also known as CD274 molecule)-expressing head and neck squamous cell carcinoma (HNSCC) in recent KEYNOTE-048 trial. However, associated changes in the tumor microenvironment (TME) and underlying mechanisms remain elusive. Oral tumors in C57/BL6 mice were induced by administering 7,12-dimethylbenzanthracene into the buccal mucosa...
March 21, 2024: Molecular Oncology
Yasmin Yu, Madhumita Bogdan, Muhammad Zaeem Noman, Santiago Parpal, Elisabetta Bartolini, Kris Van Moer, Simone Caroline Kleinendorst, Kristine Bilgrav Saether, Lionel Trésaugues, Camilla Silvander, Johan Lindström, Jodi Simeon, Mary Jane Timson, Hikmat Al-Hashimi, Bryan D Smith, Daniel L Flynn, Andrey Alexeyenko, Jenny Viklund, Martin Andersson, Jessica Martinsson, Katja Pokrovskaja Tamm, Angelo De Milito, Bassam Janji
An immunosuppressive tumor microenvironment promotes tumor growth and is one of the main factors limiting the response to cancer immunotherapy. We have previously reported that inhibition of vacuolar protein sorting 34 (VPS34), a crucial lipid kinase in the autophagy/endosomal trafficking pathway, decreases tumor growth in several cancer models, increases infiltration of immune cells and sensitizes tumors to anti-programmed cell death protein 1/programmed cell death 1 ligand 1 therapy by upregulation of C-C motif chemokine 5 (CCL5) and C-X-C motif chemokine 10 (CXCL10) chemokines...
March 20, 2024: Molecular Oncology
Haihua Yuan, Renjie Cai, Biying Chen, Qian Wang, Mengting Wang, Junyi An, Weishu An, Ye Tao, Jianxiu Yu, Bin Jiang, Yanjie Zhang, Ming Xu
Androgen-regulated DNA damage response (DDR) is one of the essential mechanisms in prostate cancer (PCa), a hormone-sensitive disease. The heterogeneous nuclear ribonucleoprotein K (hnRNPK)-homology splicing regulatory protein known as far upstream element-binding protein 2 (KHSRP) is an RNA-binding protein that can attach to AU-rich elements in the 3' untranslated region (3'-UTR) of messenger RNAs (mRNAs) to mediate mRNA decay and emerges as a critical regulator in the DDR to preserve genome integrity...
March 19, 2024: Molecular Oncology
Olivier Romito, Aude Lemettre, Aurélie Chantôme, Ophélie Champion, Noémie Couty, Lobna Ouldamer, Nadine Hempel, Mohamed Trebak, Caroline Goupille, Marie Potier-Cartereau
No data are currently available on the functional role of small conductance Ca2+ -activated K+ channels (SKCa) in ovarian cancer. Here, we characterized the role of SK2 (KCa2.2) in ovarian cancer cell migration and chemosensitivity. Using the selective non-cell-permeant SK2 inhibitor Lei-Dab7, we identified functional SK2 channels at the plasma membrane, regulating store-operated Ca2+ entry (SOCE) in both cell lines tested (COV504 and OVCAR3). Silencing KCNN2 with short interfering RNA (siRNA), or blocking SK2 activity with Lei-Dab7, decreased cell migration...
March 13, 2024: Molecular Oncology
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