Axl is a novel target of withaferin A in the induction of apoptosis and the suppression of invasion

• Withaferin A inhibits phosphorylation of Axl and STAT3.
• Withaferin A down-regulates Axl expression in a lysosome-dependent manner.
• Withaferin A suppresses rhGas6-induced cell migration.
• Overexpression of Axl attenuates withaferin A-induced apoptosis.

Withaferin A, a withanolide derived from the medicinal plant Withania somnifera, has been reported to exhibit anti-tumorigenic activity against various cancer cells. In this study, we show that withaferin A inhibits the constitutive and recombinant human growth-arrest-specific protein 6 (rhGas6)-induced phosphorylation of Axl and STAT3. In addition, withaferin A also induces the down-regulation of Axl protein expression in a lysosome-dependent manner and inhibits rhGas6-induced wound healing and cell migration. Furthermore, the overexpression of Axl attenuates withaferin A-induced apoptosis. Taken together, the data from the present study indicate that the withaferin A-mediated down-regulation of the Gas6/Axl signaling pathway mediates the inhibition of cell migration and the induction of apoptosis.