Asparagine Synthetase in Cancer: Beyond Acute Lymphoblastic Leukemia

Abstract

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.

Keywords: acute lymphoblastic leukemia; asparagine; asparagine synthetase; cancer; glutamine.

Figure 1

Mechanisms involved in resistance to L-asparaginase. Upper panel, ASNase catalyzes the hydrolysis of asparagine (Asn) into aspartate (Asp) and of glutamine (Gln) into glutamate (Glu), driving low-ASNS cells to cell death. Central panel, ASNS induction and increase in GS protein expression are not able to rescue ASNase-induced apoptotis due to poor availability of their substrates Asp and Glu. Lower panel, the overexpression of EAAT1 or EAAT3 anionic amino acid transporters provides Glu (for the synthesis of Gln, through Glutamine Syntethase) and Asp (27). Both Gln and Asp are needed for Asn synthesis via ASNS and for an effective cell rescue. The model is mainly based on data obtained with prostate cancer cells by Sun et al. (27) but it may apply to other low-ASNS cancers.

Figure 2

The potential metabolic advantages of low and high expression of Asparagine Synthetase (ASNS) in cancer cells. (Left) Low ASNS expression, caused by promoter methylation, renders cells dependent on asparagine (Asn) uptake, while increasing aspartate (Asp) availability for the synthesis of nucleotides, other non-essential amino acids (NEAA), and energy production. Transporters most likely involved in Asn uptake are shown, although the indication is largely hypothetical in most cancer models. (Right) Increased ASNS transcription, due to either gene amplification or high ATF4 activity, raises Asn production that enhances protein synthesis and cell growth by activating the mammalian target of rapamycin complex 1 (mTORC1) through the influx of essential amino acids mediated by exchange through a LAT transporter (72), tentatively identified as LAT2. Other transporters have been omitted for clarity. However, other mechanisms, such as direct effects of Asn or Asp on mTORC1, should not be excluded but the information available (11, 68, 72) does not allow generalizable conclusions. See text for discussion.