Asparagine Synthetase (ASNS) catalyzes the synthesis of the non-
essential amino acid asparagine (Asn) from
aspartate (Asp) and
glutamine (Gln). ASNS expression is highly regulated at the transcriptional level, being induced by both the
Amino Acid Response (AAR) and the Unfolded Protein Response (UPR) pathways. Lack of ASNS
protein expression is a hallmark of
Acute Lymphoblastic Leukemia (ALL) blasts, which, therefore, are auxotrophic for Asn. This peculiarity is the rationale for the use of bacterial L-
Asparaginase (ASNase) for ALL
therapy, the first example of anti-
cancer treatment targeting a
tumor-specific metabolic feature. Other hematological and solid
cancers express low levels of ASNS and, therefore, should also be Asn auxotrophs and ASNase sensitive. Conversely, in the last few years, several reports indicate that in some
cancer types ASNS is overexpressed, promoting cell proliferation, chemoresistance, and a metastatic behavior. However, enhanced ASNS activity may constitute a metabolic vulnerability in selected
cancer models, suggesting a variable and
tumor-specific role of the
enzyme in
cancer. Recent evidence indicates that, beyond its canonical role in
protein synthesis, Asn may have additional regulatory functions. These observations prompt a re-appreciation of ASNS activity in the biology of normal and
cancer tissues, with particular attention to the fueling of Asn exchange between
cancer cells and the tumor microenvironment.