A novel chemical inhibitor suppresses breast cancer cell growth and metastasis through inhibiting HPIP oncoprotein

Abstract

Abstract Increasing evidence suggests the pivotal role of hematopoietic pre-B-cell leukemia transcription factor (PBX)-interacting protein (HPIP/PBXIP1) in cancer development and progression, indicating that HPIP inhibition may be a promising target for cancer therapy. Here, we screened compounds inhibiting breast cancer cell proliferation with HPIP fused with green fluorescent protein as a reporter. A novel agent named TXX-1-10 derived from rimonabant, an antagonist of cannabinoid receptor 1 with anticancer effects, has been discovered to reduce HPIP expression and has greater inhibitory effects on breast cancer cell growth and metastasis in vitro and in vivo than rimonabant. TXX-1-10 regulates HPIP downstream targets, including several important kinases involved in cancer development and progression (e.g., AKT, ERK1/2, and FAK) as well as cell cycle-, apoptosis-, migration-, and epithelial-to-mesenchymal transition (EMT)-related genes. Consistent with the results of anticancer effects, genome-wide RNA sequencing indicated that TXX-1-10 has more significant effects on regulation of the expression of genes related to DNA replication, cell cycle, apoptosis, cell adhesion, cell migration, and invasion than rimonabant. In addition, TXX-1-10 significantly regulated genes associated with the cell growth and extracellular matrix organization, many of which were shown to be regulated by HPIP. Moreover, compared with rimonabant, TXX-1-10 greatly reduces blood-brain barrier penetrability to avoid adverse central depressive effects. These findings suggest that HPIP inhibition may be a useful strategy for cancer treatment and TXX-1-10 is a promising candidate drug for cancer therapy.