Chemical Interrogation of Nuclear Size Identifies Compounds with Cancer Cell Line-Specific Effects on Migration and Invasion

Background: Lower survival rates for many cancer
types correlate with changes in nuclear size/scaling in a tumor-type/tissue-specific
manner. Hypothesizing that such changes might confer an advantage
to tumor cells, we aimed at the identification of commercially available
compounds to guide further mechanistic studies. We therefore screened
for Food and Drug Administration (FDA)/European Medicines Agency (EMA)-approved
compounds that reverse the direction of characteristic tumor nuclear
size changes in PC3, HCT116, and H1299 cell lines reflecting, respectively,
prostate adenocarcinoma, colonic adenocarcinoma, and small-cell squamous
lung cancer. Results: We found distinct, largely
nonoverlapping sets of compounds that rectify nuclear size changes
for each tumor cell line. Several classes of compounds including,
e.g., serotonin uptake inhibitors, cyclo-oxygenase inhibitors, β-adrenergic
receptor agonists, and Na+/K+ ATPase inhibitors,
displayed coherent nuclear size phenotypes focused on a particular
cell line or across cell lines and treatment conditions. Several compounds
from classes far afield from current chemotherapy regimens were also
identified. Seven nuclear size-rectifying compounds selected for further
investigation all inhibited cell migration and/or invasion. Conclusions: Our study provides (a) proof of concept that
nuclear size might be a valuable target to reduce cell migration/invasion
in cancer treatment and (b) the most thorough collection of tool compounds
to date reversing nuclear size changes specific to individual cancer-type
cell lines. Although these compounds still need to be tested in primary
cancer cells, the cell line-specific nuclear size and migration/invasion
responses to particular drug classes suggest that cancer type-specific
nuclear size rectifiers may help reduce metastatic spread.