title: Bifunctional fused polypeptide inhibits the growth and metastasis of breast cancer.
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.
authors.affiliation: Medical Molecular Diagnostics Key Laboratory of Guangdong, Guangdong Medical University, Dongguan, Guangdong, People's Republic of China ; Department of Biochemistry and Molecular Biology, Guangdong Medical University, Dongguan, Guangdong, People's Republic of China ; Department of Clinical Biochemistry, Guangdong Medical University, Dongguan, Guangdong, People's Republic of China.
authors.forename: Ai-Ling
authors.initials: AL
authors.lastname: Liang
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute, Chinese Academy of Medical Sciences, Beijing, People's Republic of China.
authors.forename: Hai-Li
authors.initials: HL
authors.lastname: Qian
authors.affiliation: Medical Molecular Diagnostics Key Laboratory of Guangdong, Guangdong Medical University, Dongguan, Guangdong, People's Republic of China ; Department of Biochemistry and Molecular Biology, Guangdong Medical University, Dongguan, Guangdong, People's Republic of China ; Department of Clinical Biochemistry, Guangdong Medical University, Dongguan, Guangdong, People's Republic of China.
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Zhang
authors.affiliation: Medical Molecular Diagnostics Key Laboratory of Guangdong, Guangdong Medical University, Dongguan, Guangdong, People's Republic of China ; Department of Biochemistry and Molecular Biology, Guangdong Medical University, Dongguan, Guangdong, People's Republic of China ; Department of Clinical Biochemistry, Guangdong Medical University, Dongguan, Guangdong, People's Republic of China.
authors.forename: Ning
authors.initials: N
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute, Chinese Academy of Medical Sciences, Beijing, People's Republic of China.
authors.forename: Hai-Juan
authors.initials: HJ
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute, Chinese Academy of Medical Sciences, Beijing, People's Republic of China.
authors.forename: Xi-Ting
authors.initials: XT
authors.lastname: Men
authors.affiliation: Electroencephalogram Room, Guangdong Medical University Affiliated Hospital, Zhanjiang, Guangdong, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Qi
authors.affiliation: Department of Orthopedics, Guangdong Medical University Affiliated Hospital, Zhanjiang, Guangdong, People's Republic of China.
authors.forename: Ping-Ping
authors.initials: PP
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute, Chinese Academy of Medical Sciences, Beijing, People's Republic of China.
authors.forename: Ming
authors.initials: M
authors.lastname: Fu
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute, Chinese Academy of Medical Sciences, Beijing, People's Republic of China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Liang
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute, Chinese Academy of Medical Sciences, Beijing, People's Republic of China.
authors.forename: Chen
authors.initials: C
authors.lastname: Lin
authors.affiliation: Medical Molecular Diagnostics Key Laboratory of Guangdong, Guangdong Medical University, Dongguan, Guangdong, People's Republic of China ; Department of Biochemistry and Molecular Biology, Guangdong Medical University, Dongguan, Guangdong, People's Republic of China ; Department of Clinical Biochemistry, Guangdong Medical University, Dongguan, Guangdong, People's Republic of China.
authors.forename: Yong-Jun
authors.initials: YJ
authors.lastname: Liu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D061986:MCF-7 Cells; D008819:Mice, Nude; D010455:Peptides / Q000494:pharmacology*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C527276:CXCR4 protein, human; D010455:Peptides; D019718:Receptors, CXCR4; D011993:Recombinant Fusion Proteins; C000608794:TAT-DV1-BH3 protein
keywords: CXCR4; apoptosis; bifunctional; breast cancer; fused polypeptide; transfer