PUBLICATION

Bladder Cancer Invasion is Mediated by mTORC2-Driven Regulation of Nitric Oxide and Invadopodia Formation

Authors
Sahu, D., Huan, J., Wang, H., Sahoo, D., Casteel, D.E., Klemke, R.L., Boss, G.R., Hansel, D.E.
ID
ZDB-PUB-210825-7
Date
2021
Source
The American journal of pathology   191(12): 2203-2218 (Journal)
Registered Authors
Klemke, Richard
Keywords
Invadopodia, NOS, bladder cancer, mTORC2, mammalian target of rapamycin, nitric oxide, urothelial carcinoma
MeSH Terms
  • Animals
  • Carcinoma, Transitional Cell/genetics
  • Carcinoma, Transitional Cell/metabolism
  • Carcinoma, Transitional Cell/pathology
  • Embryo, Nonmammalian
  • Humans
  • Mechanistic Target of Rapamycin Complex 2/physiology*
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Nitric Oxide/metabolism*
  • Podosomes/genetics
  • Podosomes/metabolism*
  • Podosomes/pathology
  • Tumor Cells, Cultured
  • Urinary Bladder Neoplasms/genetics
  • Urinary Bladder Neoplasms/metabolism
  • Urinary Bladder Neoplasms/pathology*
  • Zebrafish/embryology
PubMed
34428425 Full text @ Am. J. Pathol.
Abstract
Bladder cancer invasion depends on mammalian target of rapamycin complex-2 (mTORC2) activity, although the downstream mTORC2 effectors that mediate this effect have not been fully defined. One potential downstream effector is the arginine derivative nitric oxide (NO). Here, we identified a stage-associated increase in the expression of NO-generating enzymes endothelial NOS (eNOS) and inducible NOS (iNOS) in human bladder cancer. Reduction of NOS activity by pharmacological inhibition or silencing of NOS enzymes reduced cancer cell invasion, with similar effects observed using the NO scavenger cobinamide. By contrast, enhanced invasion was seen with both the NO donor Deta-NONOate and an analog of the downstream NO second messenger cGMP. We next evaluated NOS expression in invadopodia, which are cellular protrusions that form the invasive tips of cancer cells. Invadopodia were enriched in both iNOS protein and mTORC2 activity, and invadopodia formation was increased by Deta-NONOate and decreased by cobinamide and ablation of mTORC2 activity. mTORC2 additionally increased expression of iNOS. Using a zebrafish model, injection of iNOS- or rictor-silenced cells reduced the frequency of bladder cancer cell metastasis in zebrafish. These results indicate that mTORC2 can mediate bladder cancer cell invasion through increased iNOS expression, resulting in increased NO and cGMP production in invadopodia and further propagation of invadopodia formation.
Genes / Markers
Figures
Show all Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping