Bifunctional fused polypeptide inhibits the growth and metastasis of breast cancer

Abstract

Ai-Ling Liang,1–3,* Hai-Li Qian,4,* Ting-Ting Zhang,1–3 Ning Zhou,1–3 Hai-Juan Wang,4 Xi-Ting Men,4 Wei Qi,5 Ping-Ping Zhang,6 Ming Fu,4 Xiao Liang,4 Chen Lin,4 Yong-Jun Liu1–3 1Medical Molecular Diagnostics Key Laboratory of Guangdong, 2Department of Biochemistry and Molecular Biology, 3Department of Clinical Biochemistry, Guangdong Medical University, Dongguan, Guangdong, 4State Key Laboratory of Molecular Oncology, Cancer Institute, Chinese Academy of Medical Sciences, Beijing, 5Electroencephalogram Room, 6Department of Orthopedics, Guangdong Medical University Affiliated Hospital, Zhanjiang, Guangdong, People’s Republic of China *These authors contributed equally to this study Abstract: Breast cancer is the most common cancer and the leading cause of cancer-related death among women worldwide, with urgent need to develop new therapeutics. Targeted therapy is a promising strategy for breast cancer therapy. Stromal-derived factor-1/CXC chemokine receptor 4 (CXCR4) has been implicated in the metastasis of breast cancer, which renders it to be therapeutic target. This study aimed to evaluate the anticancer effect of fused TAT–DV1–BH3 polypeptide, an antagonist of CXCR4, and investigate the underlying mechanism for the cancer cell-killing effect in the treatment of breast cancer in vitro and in vivo. This results in a potent inhibitory effect of fused TAT–DV1–BH3 polypeptide on tumor growth and metastasis in nude mice bearing established MDA-MB-231 tumors. Fused TAT–DV1–BH3 polypeptide inhibited the proliferation of MDA-MB-231 and MCF-7 cells but did not affect that of HEK-293 cells. The fused TAT–DV1–BH3 polypeptide colocalized with mitochondria and exhibited a proapoptotic effect through the regulation of caspase-9 and -3. Furthermore, the fused TAT–DV1–BH3 polypeptide suppressed the migration and invasion of the highly metastatic breast cancer cell line MDA-MB-231 in a concentration-dependent manner. Notably, the DV1-mediated inhibition of the stromal-derived factor-1/CXCR4 pathway contributed to the antimetastasis effect, evident from the reduction in the level of phosphoinositide 3 kinase and matrix metalloproteinase 9 in MDA-MB-231 cells. Collectively, these results indicate that the apoptosis-inducing effect and migration- and invasion-suppressing effect explain the tumor regression and metastasis inhibition in vivo, with the involvement of caspase- and CXCR4-mediated signaling pathway. The data suggest that the fused TAT–DV1–BH3 polypeptide is a promising agent for the treatment of breast cancer, and more studies are warranted to fully elucidate the therapeutic targets and molecular mechanism. Keywords: bifunctional, fused polypeptide, CXCR4, breast cancer, apoptosis, transfer