Wogonoside induces depalmitoylation and translocation of PLSCR1 and N-RAS in primary acute myeloid leukaemia cells

Abstract

Acute myeloid leukaemia (AML) comprises a range of disparate genetic subtypes, involving complex gene mutations and specific molecular alterations. Post-translational modifications of specific proteins influence their translocation, stability, aggregation and even leading disease progression. Therapies that target to post-translational modification of specific proteins in cancer cells represent a novel treatment strategy. Non-homogenous subcellular distribution of PLSCR1 is involved in the primary AML cell differentiation. However, the nuclear translocation mechanism of PLSCR1 remains poorly understood. Here, we leveraged the observation that nuclear translocation of PLSCR1 could be induced during wogonoside treatment in some primary AML cells, despite their genetic heterogeneity that contributed to the depalmitoylation of PLSCR1 via acyl protein thioesterase 1 (APT-1), an enzyme catalysing protein depalmitoylation. Besides, we found a similar phenomenon on another AML-related protein, N-RAS. Wogonoside inhibited the palmitoylation of small GTPase N-RAS and enhanced its trafficking into Golgi complex, leading to the inactivation of N-RAS/RAF1 pathway in some primary AML cells. Taken together, our findings provide new insight into the mechanism of wogonoside-induced nuclear translocation of PLSCR1 and illuminate the influence of N-RAS depalmitoylation on its Golgi trafficking and RAF1 signalling inactivation in AML.

Keywords: N-RAS; PLSCR1; acute myeloid leukaemia; depalmitoylation; translocation; wogonoside.