Bladder Cancer Invasion Is Mediated by Mammalian Target of Rapamycin Complex 2-Driven Regulation of Nitric Oxide and...

Area of Science:

• Oncology
• Molecular Biology
• Cell Biology

Background:

• Bladder cancer invasion is linked to mammalian target of rapamycin complex 2 (mTORC2) signaling.
• Downstream effectors of mTORC2 in bladder cancer invasion are not fully understood.
• Nitric oxide (NO) is a potential mediator of cancer cell invasion.

Purpose of the Study:

• To investigate the role of nitric oxide (NO) synthase (NOS) enzymes and NO in bladder cancer cell invasion.
• To elucidate the relationship between mTORC2 activity, NOS expression, and invadopodia formation in bladder cancer.

Main Methods:

• Assessed NOS enzyme expression (eNOS, iNOS) in human bladder cancer tissues.
• Utilized pharmacologic inhibitors, gene silencing, and NO scavengers/donors to modulate NOS activity.
• Examined invadopodia formation and mTORC2 activity in cancer cells.
• Employed a zebrafish model to evaluate the in vivo effect of iNOS and mTORC2 on metastasis.

Main Results:

• Stage-associated increase in eNOS and iNOS expression observed in bladder cancer.
• Inhibition of NOS activity or NO scavenging reduced cancer cell invasion.
• NO donors and cGMP analogs enhanced cancer cell invasion.
• Invadopodia were enriched with iNOS and mTORC2; mTORC2 increased iNOS expression.
• Silencing iNOS or mTORC2 components (rictor) reduced metastasis in zebrafish.

Conclusions:

• mTORC2 promotes bladder cancer cell invasion via upregulation of iNOS.
• Increased NO and cGMP production, particularly in invadopodia, drives invasion.
• Targeting the mTORC2-iNOS pathway may offer therapeutic strategies for bladder cancer.