Colorectal cancer (CRC) is among the most common cancers worldwide and remains a leading cause of cancer-related morbidity and mortality despite significant advances in CRC treatment in recent years.
The p21-activated kinase (PAK) family of serine/threonine kinases displays a diverse function in growth factor signalling, cytoskeleton remodelling, cell survival, oncogenic transformation and gene transcription. Over-expression of PAK1 is frequently observed in CRC and is closely correlated with tumour progression and therapeutic resistance. These observations in addition to a central role of PAK1 in cancer cell signalling suggest that PAK1 is an attractive drug target.
We reported here for the first time, the anti-malarial quassinoid, Glaucarubinone inhibits CRC growth both in vitro and in vivo by down-regulation of PAK1. We have demonstrated that Glaucarubinone, as well as its analogue Ailanthinone, attenuated CRC cell proliferation and migration/invasion at nanomolar concentrations. Glaucarubinone also significantly reduced the xenograft growth of CRC cells in SCID mouse. The PAK1 phosphorylation, expression and kinase activity was significantly decreased with Glaucarubinone treatment of CRC cell and tumour tissue extracts.
In conclusion, we have demonstrated the potential of Glaucarubinone in inhibiting CRC growth through down-regulating PAK1. This provides the rationale for further development of PAK1-based drug targeting in CRC treatment.