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

Pengyun Li,Qinong Ye,Song Li,Xu Cai,Shengjie Cao,Yanan Zhang,Lulu Zhou,Zhibing Zheng,Jie Liu,Zefei Jiang,Lihua Ding,Jianbin Li,Yubing Huang

doi:10.1038/s41420-021-00580-3

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.

Highlights

As one of the most common heterogeneous diseases among women, breast cancer highly displays diversification in terms of its presentation, disease progression, pathological characteristics, and clinical response [1, 2]
RNA-Seq reveals TXX-1-10 regulating expression of genes related to cell growth and metastasis Given TXX-1-10 as a potent tumor-suppressive agent, we TXX-1-10 induces G1 cell cycle arrest and apoptosis in breast cancer cells Since anticancer drugs eliminate tumor cells predominantly by triggering apoptosis and inducing cell cycle arrest [20, 21], we examined the effect of TXX-1-10 on breast cancer cell cycle and investigated the impact of TXX-1-10 on global gene expression using RNA sequencing (RNA-seq) (Fig. 5A and Supplementary Fig. 7A, B)
Genomewide RNA sequencing indicated TXX-1-10 has more significant effects on the regulation of the expression of genes involved in cancer cell growth and metastasis than rimonabant

Summary

Introduction

As one of the most common heterogeneous diseases among women, breast cancer highly displays diversification in terms of its presentation, disease progression, pathological characteristics, and clinical response [1, 2]. The PI3K/Akt/mTOR and RAS-RAF-MEK-ERK signaling pathways are hyperactivated in a high percentage of tumors, including epithelial ovarian, glioblastoma, breast, lung, and renal cancers [5,6,7]. Increasing studies have been focused on the development of small-molecule inhibitors targeting components of PI3K/Akt/ mTOR and RAS-RAF-MEK-ERK signaling as cancer therapeutics [8]. AKT inhibition using small-molecule inhibitors, such as AZD5363 and GSK690693 have been studied in preclinical setup and evaluated in many clinical trials to block human tumors [9]. Clinical efficacy using single molecules directly inhibiting Akt or ERK signaling was shown to have a limited pharmaceutical effect on cancer due to the induction of resistance [9, 11]. Several therapies have been discontinued because of the development of side effects, such as rash, hyperglycemia, and hemolytic toxicity after intravenous injection [6], implying the need for more innovative approaches to achieve inhibition of Akt or ERK signaling for cancer treatment with minimal side effects

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Results

Conclusion