Concurrent upregulation of autophagic flux and induction of the SQSTM1/p62-VCAM-1 axis deter radiosensitivity of triple-negative breast cancer cells

Abstract

Triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer (BC) with higher incidence rates in India. Ionizing radiation (IR) is a key component of TNBC treatment regimens. However, overall suboptimal response during the course of multiple repeat radiotherapy with eventual attainment of radioresistance remains a major challenge for this oncologic treatment modality. To overcome this limitation, it is important to understand molecular signatures that drive cells to transform into non-responsive populations against radiation therapy. Here, we demonstrate a constitutively high basal level of autophagy in TNBC cells, which might contribute to their relatively lower sensitivity to radiation-induced cell death. We also observed an elevated level of p62 in TNBC cells, which is regulated independently of autophagic flux. Concurrent upregulation of p62 and basal level of autophagy were found to be the driving forces in acquiring radioresistance in breast cancer cells. Ectopic expression of p62 enabled breast cancer cells to proliferate rapidly with enhanced migration potential. Reciprocally, posttranscriptional or pharmacological inhibition of p62 prevented the proliferation and migration potential of TNBC cells. Our high-throughput next-generation sequencing (NGS) data revealed VCAM-1 as a key mediator in p62-driven cell proliferation and acquired radioresistance. Likewise, impairment of autophagic flux, either by pharmacological inhibitors (CQ and bafA1) or by genetic deletion of ATG5, led to reversal of radioresistance. Collectively, our data highlight that an elevated basal level of autophagy with co-induction of p62 de novo protein synthesis confers radioresistance in TNBC.