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.
Competing Interest Statement
Prof. Nephi Stella is employed by Stella Consulting LLC. The terms of this arrangement have been reviewed and approved by the University of Washington in accordance with its policies governing outside work and financial conflicts of interest in research.
Abbreviations
- AV
- annexin-V
- CIN
- chromosomal instability
- DEG
- differentially expressed
- ECAR
- extracellular acidification rate
- ISR
- integrated stress response
- MTs
- microtubules
- MTAs
- microtubule targeting agents
- MRPs
- mitochondrial ribosomal proteins
- MDC
- monodansylcadaverine
- NOC
- nocodazole
- P-P53
- phosphorylated P53
- OXPHOS
- oxidative phosphorylation
- OCR
- oxygen consumption rate
- PGCC
- polyploid giant cancer cells
- PCA
- Principal Component Analysis
- PI
- propidium iodide
- SAC
- spindle assembly checkpoint
- TGI
- total growth inhibition
- UMAP
- Uniform Manifold Approximation and Projection