Targeting Taspase1 for Cancer Therapy—Letter Free

We read with interest the article by Chen and colleagues (1), identifying a potential Taspase1 inhibitor by using a cellular translocation assay similar to the one described by Bier and colleagues (2). These results impressively underline the power of cell-based screening, as previous attempts to identify effective small-molecule Taspase1 inhibitors by in silico or in vitro assays failed. However, one is wondering why screening was conducted in HEK293T cells, which do not express measurable levels of Taspase1 (3). Also, the results of the Ala-scan mutagenesis question the previously published Taspase1 consensus motif (2). The authors claim the critical importance of isoleucine at position P5, although the Taspase1 target USF2 contains an aspartate at P5 (2). Collectively, these factors might have contributed to the fact that only one chemical inhibitor, NSC48300, was identified, showing Taspase1 specificity in in vitro assays. Albeit the authors show that NSC48300 inhibited the growth of breast and brain tumors in murine models, the question of high interest remains that whether this activity is causally based on the inhibition of Taspase1 alone? Notably, besides its reported growth inhibition of numerous tumor cell lines, NSC48300 interfered with cell migration and invasion (4) and was patented as an antiangiogenic compound (5). This activity of the arsenic compound is further underlined by the results of the tail vein injection experiments, which might indicate potential limitations in the clinical use of NSC48300.

Although we appreciate the importance of the work for the relevance of Taspase1 in solid tumors, future works need to define the molecular mechanism how NSC48300 inhibits Taspase1 and whether Taspase1-independent effects of NSC48300 contribute to its antitumoral activity. Hence, the direct targets of Taspase1 responsible for its tumor-promoting activity need to be identified before the (pre)clinical exploitation of NSC48300 or related compounds by industry and academia.

See the Response, p. 2913

No potential conflicts of interest were disclosed.