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A recent study by Kim et al.1 has investigated the antitumor effects of argininosuccinate synthetase 1 (ASS1) in hepatocellular carcinoma (HCC) cells. In this study, the authors demonstrate that an increase in L-arginine levels, which is mediated by ASS1 in HCC, increases the sensitivity of HCC cells to the cytotoxic effects of cisplatin in the concentration range of 5 to 10 mM of L-arginine.1 In turn, this increase in L-arginine levels enhances the cisplatin-induced apoptosis of HCC cells.1 Additionally, Larginine inhibits the expression of pyruvate kinase muscle isoforms 1 and 2 in HCC cells, which results in the suppression of aerobic glycolysis - a process that is essential for the high energy demand of rapidly proliferating cancer cells. This inhibition further enhances the cytotoxic effects of L-arginine in a concentration-dependent manner in these cells.1 Ultimately, the expression of ASS1 in HCC cells results in the inhibition of key signaling pathways, including the phosphoinositide 3-kinase/protein kinase B and mammalian target of rapamycin pathways, in all types of cells, regardless of their ASS1 expression levels. Additionally, ASS1 expression suppresses the mitogen-activated protein kinase pathway in both ASS1-high and ASS1-low cells.1 This collective inhibition of these critical pathways ultimately leads to the suppression of cell proliferation and survival. Furthermore, this study demonstrates that L-arginine impedes wound healing and colony formation in HCC cells, thereby attenuating the metastatic potential of these cells and reducing the likelihood of metastasis. Additionally, the increase in ASS1 expression induces the upregulation of nitric oxide synthase, leading to nitric oxide (NO) production. NO is cytotoxic because it induces oxidative stress and DNA damage in cells, thereby triggering apoptosis. This mechanism contributes to the cytotoxic effects of L-arginine and promotes the apoptosis of HCC cells.1 In conclusion, the key finding of the study by Kim et al.1 is as follows: ASS1 enhances cytotoxicity in HCC cells through both increased NO production and elevated L-arginine levels while also inhibiting metastasis by reducing cellular infiltration and migration (Fig. 1).
As the authors have mentioned, this finding, which pertains to the antitumor effects of ASS1 in HCC, is consistent with the results of previous studies conducted by their research group using human samples. Although statistical significance was not observed, an analysis conducted on tissue samples from 58 patients with HCC revealed that in the group of patients with higher ASS1 expression in tumor tissues than adjacent peritumoral tissues, the 10-year overall survival rate after surgical resection showed a trend toward better prognosis.2 Furthermore, in HCC cells cultured as three-dimensional spheroids, overexpression of ASS1 was shown to exert antitumor effects independently of p53 and arginine metabolism by activating the protein kinase RNA-like endoplasmic reticulum kinase /eukaryotic translation initiation factor 2 alpha/activating transcription factor 4/C/EBP homologous protein signaling pathway as part of the endoplasmic reticulum stress response, which ultimately led to cell death and confirmed the antitumor role of ASS1.2
Furthermore, another study has clinically demonstrated the inhibitory effect of ASS1 on HCC, with the underlying mechanism being well established. Tumor microarray immunohistochemistry results from 225 patients with HCC have revealed that patients with low ASS1 expression in tumor tissues had significantly poorer overall survival and higher cumulative recurrence rates than those with high ASS1 expression.3 This effect is likely due to the inhibitory role of ASS1 in metastasis. ASS1 has been shown to suppress the signal transducer and activator of transcription 3 signaling pathway in HCC, which in turn reduces the expression of inhibitor of differentiation 1, a key factor involved in metastasis. Therefore, the inhibition of ASS1 expression ultimately inhibits cancer cell migration and invasion, reinforcing the role of ASS1 in suppressing HCC metastasis.3
Other studies have provided further evidence supporting the inhibitory role of ASS1 in HCC. One such study identified that LINC01234, a long non-coding RNA associated with aspartate metabolism, is highly expressed in HCC, and patients with elevated levels of LINC01234 exhibited poorer prognosis.4 LINC01234 suppresses ASS1 expression by binding to its promoter region and inhibiting transcription factors such as p53, leading to increased aspartate levels that activate the mammalian target of rapamycin pathway, thereby promoting tumor proliferation, metastasis, and drug resistance.4 This evidence suggests that targeting LINC01234 could enhance ASS1’s tumor-suppressive effects and improve HCC treatment outcomes.
These studies suggested that high ASS1 expression in HCC regulates disease progression through both direct and indirect mechanisms. ASS1 enhances cytotoxicity by upregulating NO synthase, increasing NO production, and inducing cell death. Indirectly, ASS1 elevates L-arginine levels, boosts cytotoxicity via various signaling pathways, and reduces metastatic potential. These effects highlight ASS1 as a key regulator in HCC management, inhibiting tumor growth and metastasis and making it a promising therapeutic target.
The anticancer effects of L-arginine on hepatocytes are not limited to HCC cells. Within the HCC tumor microenvironment, arginine depletion occurs because of the activity of arginase-1 expressed by CX3CR1+ macrophages. This depletion suppresses the proliferation of antitumor CD8+ T cells, impairing their ability to mount an effective immune response.5 Thus, L-arginine not only exerts direct inhibitory effects on HCC cells but also enhances the function of immune cells within the tumor microenvironment, thereby promoting tumor cell death (Fig. 1). As demonstrated in previous studies, increasing L-arginine levels in T cells induces metabolic changes, including a shift from glycolysis to oxidative phosphorylation in activated T cells. This metabolic reprogramming results in improved T-cell survival and enhanced antitumor activity.6 Therefore, the ability of L-arginine to inhibit tumor growth and enhance immune cell function makes it a promising strategy for boosting the effectiveness of immune-based therapies in HCC.
In conclusion, the anticancer effects of L-arginine and ASS1 in HCC offer promising therapeutic targets for HCC. These effects involve direct cytotoxicity and inhibition of tumor cell proliferation and modulate the tumor microenvironment and enhance immunological responses. Given their dual roles in targeting HCC cells and influencing immune function, L-arginine and ASS1 hold potential as key components for the development of novel therapies to improve HCC treatment outcomes.
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