Homoharringtonine promotes BCR‑ABL degradation through the p62‑mediated autophagy pathway.

Drug resistance to tyrosine kinase inhibitors (TKIs) is currently a clinical problem in patients with chronic myelogenous leukemia (CML). Homoharringtonine (HHT) is an approved treatment for adult patients with chronic- or accelerated-phase CML who are resistant to TKIs and other therapies; however, the underlying mechanisms remain unclear. In the present study, HHT treatment demonstrated induction of apoptosis in imatinib-resistant K562G cells by using MTS assay and western blotting, and BCR-ABL protein was reduced. CHX chase assay revealed that HHT induced degradation of the BCR-ABL protein, which could be reversed by autophagy lysosome inhibitors Baf-A1 and CQ. Next, HHT treatment confirmed the induction of autophagy in K562G cells, and silencing the key autophagic proteins ATG5 and Beclin-1 inhibited the degradation of the BCR-ABL protein and cytotoxicity. In addition, autophagic receptor p62/SQSTM1(p62) participated during the autophagic degradation of BCR-ABL induced by HHT, and this was confirmed by co-immunoprecipitation, in which HHT enhanced the ubiquitination of the BCR-ABL protein and promoted its binding to p62. In conclusion, HHT induced p62-mediated autophagy in imatinib-resistant CML K562G cells, thus promoting autophagic degradation of the BCR-ABL protein and providing a novel strategy for the treatment of TKI-resistant CML.