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1.
J Transl Med ; 22(1): 441, 2024 May 10.
Article in English | MEDLINE | ID: mdl-38730481

ABSTRACT

Microtubule targeting agents (MTAs) are commonly prescribed to treat cancers and predominantly kill cancer cells in mitosis. Significantly, some MTA-treated cancer cells escape death in mitosis, exit mitosis and become malignant polyploid giant cancer cells (PGCC). Considering the low number of cancer cells undergoing mitosis in tumor tissues, killing them in interphase may represent a favored antitumor approach. We discovered that ST-401, a mild inhibitor of microtubule (MT) assembly, preferentially kills cancer cells in interphase as opposed to mitosis, a cell death mechanism that avoids the development of PGCC. Single cell RNA sequencing identified mRNA transcripts regulated by ST-401, including mRNAs involved in ribosome and mitochondrial functions. Accordingly, ST-401 induces a transient integrated stress response, reduces energy metabolism, and promotes mitochondria fission. This cell response may underly death in interphase and avoid the development of PGCC. Considering that ST-401 is a brain-penetrant MTA, we validated these results in glioblastoma cell lines and found that ST-401 also reduces energy metabolism and promotes mitochondria fission in GBM sensitive lines. Thus, brain-penetrant mild inhibitors of MT assembly, such as ST-401, that induce death in interphase through a previously unanticipated antitumor mechanism represent a potentially transformative new class of therapeutics for the treatment of GBM.


Subject(s)
Cell Death , Giant Cells , Interphase , Microtubules , Polyploidy , Humans , Interphase/drug effects , Microtubules/metabolism , Microtubules/drug effects , Cell Line, Tumor , Cell Death/drug effects , Giant Cells/drug effects , Giant Cells/metabolism , Giant Cells/pathology , Mitochondrial Dynamics/drug effects , Energy Metabolism/drug effects , Glioblastoma/pathology , Glioblastoma/drug therapy , Glioblastoma/metabolism , Glioblastoma/genetics , Neoplasms/pathology , Neoplasms/drug therapy , Neoplasms/metabolism , Neoplasms/genetics , Mitochondria/metabolism , Mitochondria/drug effects , Gene Expression Regulation, Neoplastic/drug effects
2.
bioRxiv ; 2023 Oct 05.
Article in English | MEDLINE | ID: mdl-37693393

ABSTRACT

Microtubule targeting agents ( MTAs ) are commonly prescribed to treat cancers and predominantly kill cancer cells in mitosis. Significantly, some MTA-treated cancer cells can escape death in mitosis and exit mitosis, and become malignant polyploid giant cancer cells ( PGCC ). Considering the low number of malignant cells undergoing mitosis in tumor tissue, killing these cells in interphase may represent a favored antitumor approach. We discovered that ST-401, a mild inhibitor of microtubule assembly, preferentially kills cancer cells in interphase as opposed to mitosis, and avoids the development of PGCC. Single cell RNA sequencing identified mRNA transcripts regulated by ST-401, including mRNAs involved in ribosome and mitochondrial functions. Accordingly, ST-401 induces an integrated stress response and promotes mitochondria fission accompanied by a reduction in energy metabolism. This cell response may underly death in interphase and avoid the development of PGCC.

3.
Protein Sci ; 30(9): 1804-1817, 2021 09.
Article in English | MEDLINE | ID: mdl-34076319

ABSTRACT

With over 150 heritable mutations identified as disease-causative, superoxide dismutase 1 (SOD1) has been a main target of amyotrophic lateral sclerosis (ALS) research and therapeutic efforts. However, recent evidence has suggested that neither loss of function nor protein aggregation is responsible for promoting neurotoxicity. Furthermore, there is no clear pattern to the nature or the location of these mutations that could suggest a molecular mechanism behind SOD1-linked ALS. Here, we utilize reliable and accurate computational techniques to predict the perturbations of 10 such mutations to the free energy changes of SOD1 as it matures from apo monomer to metallated dimer. We find that the free energy perturbations caused by these mutations strongly depend on maturational progress, indicating the need for state-specific therapeutic targeting. We also find that many mutations exhibit similar patterns of perturbation to native and non-native maturation, indicating strong thermodynamic coupling between the dynamics at various sites of maturation within SOD1. These results suggest the presence of an allosteric network in SOD1 which is vulnerable to disruption by these mutations. Analysis of these perturbations may contribute to uncovering a unifying molecular mechanism which explains SOD1-linked ALS and help to guide future therapeutic efforts.


Subject(s)
Apoproteins/chemistry , Superoxide Dismutase-1/chemistry , Zinc/chemistry , Allosteric Regulation , Amyotrophic Lateral Sclerosis/genetics , Amyotrophic Lateral Sclerosis/metabolism , Amyotrophic Lateral Sclerosis/pathology , Apoproteins/genetics , Apoproteins/metabolism , Binding Sites , Cations, Divalent , Gene Expression , Humans , Hydrogen Bonding , Kinetics , Molecular Dynamics Simulation , Mutation , Protein Aggregates , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , Protein Multimerization , Superoxide Dismutase-1/genetics , Superoxide Dismutase-1/metabolism , Thermodynamics , Zinc/metabolism
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