Enhancing Efficacy of Albumin-Bound Paclitaxel for Human Lung and Colorectal Cancers through Autophagy Receptor Sequestosome 1 (SQSTM1)/p62-Mediated Nanodrug Delivery and Cancer therapy

Selective autophagy is a defense mechanism by which foreign pathogens and abnormal substances are processed to maintain cellular homeostasis. Sequestosome 1 (SQSTM1)/p62, a vital selective autophagy receptor, recruits ubiquitinated cargo to form autophagosomes for lysosomal degradation. Nab-PTX is an albumin-bound paclitaxel nanoparticle used in clinical cancer therapy. However, the role of SQSTM1 in regulating the delivery and efficacy of nanodrugs remains unclear. Here we showed that SQSTM1 plays a crucial role in Nab-PTX drug delivery and efficacy in human lung and colorectal cancers. Nab-PTX induces SQSTM1 phosphorylation at Ser403, which facilitates its incorporation into the selective autophagy of nanoparticles, known as nanoparticulophagy. Nab-PTX increased LC3-II protein expression, which triggered autophagosome formation. SQSTM1 enhanced Nab-PTX recognition to form autophagosomes, which were delivered to lysosomes for albumin degradation, thereby releasing PTX to induce mitotic catastrophe and apoptosis. Knockout of SQSTM1 downregulated Nab-PTX-induced mitotic catastrophe, apoptosis, and tumor inhibition in vitro and in vivo and inhibited Nab-PTX-induced caspase 3 activation via a p53-independent pathway. Ectopic expression of SQSTM1 by transfection of an SQSTM1-GFP vector restored the drug efficacy of Nab-PTX. Importantly, SQSTM1 is highly expressed in advanced lung and colorectal tumors and is associated with poor overall survival in clinical patients. Targeting SQSTM1 may provide an important strategy to improve nanodrug efficacy in clinical cancer therapy. This study demonstrates the enhanced efficacy of Nab-PTX for human lung and colorectal cancers via SQSTM1-mediated nanodrug delivery.