Inhibition of sphingolipid metabolism in osteosarcoma protects against CD151-mediated tumorigenicity

Osteosarcoma is the most common primary bone tumor, with a poor prognosis owing to the lack of efficient molecular-based targeted therapies. Previous studies have suggested an association between CD151 and distinct consequences in osteosarcoma tumorigenicity. However, the potential of CD151 as a therapeutic target has not yet been sufficiently explored. Here, we performed integrated transcriptomic and metabolomic analyses of osteosarcoma and identified sphingolipid metabolism as the top CD151-regulated pathway. CD151 regulates sphingolipid metabolism primarily through SPTCL1, the first rate-limiting enzyme in sphingolipid biosynthesis. Mechanistically, depletion of CD151 enhanced c-myc polyubiquitination and subsequent degradation. c-myc is vital for the transcriptional activation of SPTLC1. Functionally, sphingolipid synthesis and the SPTLC1 inhibitor, myriocin, significantly suppressed the clonogenic growth of CD151-overexpression cells. Importantly, myriocin selectively restrained CD151-high expression tumor growth in preclinical patient-derived xenograft models. Collectively, these data establish that CD151 is a key mediator of sphingolipid metabolism and provide a new approach to developing novel CD151-based targeted therapies for osteosarcoma.

Automated summary

This study reveals that CD151 regulates sphingolipid metabolism in osteosarcoma and can be targeted for therapy. CD151 enhances sphingolipid synthesis through SPTCL1 and inhibition of sphingolipid synthesis suppresses clonogenic growth of CD151-overexpression cells. Furthermore, myriocin, an SPTLC1 inhibitor, selectively inhibits tumor growth in CD151-high expression tumors.