Cancer development is associated with abnormal proliferation, genetic instability, cell death resistance, metabolic reprogramming, immunity evasion, and
metastasis. These alterations are triggered by genetic and epigenetic alterations in genes that control cell homeostasis. Increased reactive
oxygen and
nitrogen species (ROS, RNS) induced by different
enzymes and reactions with distinct molecules contribute to malignant transformation and
tumor progression by modifying
DNA,
proteins, and
lipids, altering their activities.
Nitric oxide synthase plays a central role in oncogenic signaling modulation and redox landscape. Overexpression of the three NOS
isoforms has been found in innumerous types of
cancer contributing to
tumor growth and development. Although the main function of NOS is the production of
nitric oxide (NO), it can be a source of ROS in some pathological conditions. Decreased
tetrahydrobiopterin (BH4) cofactor availability is involved in NOS dysfunction, leading to ROS production and reduced levels of NO. The regulation of NOSs by BH4 in
cancer is controversial since BH4 has been reported as a pro-tumoral or an antitumoral molecule. Therefore, in this review, the role of BH4 in the control of NOS activity and its involvement in the capabilities acquired along
tumor progression of different
cancers was described.