Peroxidase from foxtail millet bran exerts anti-colorectal cancer activity via targeting cell-surface GRP78 to inactivate STAT3 pathway

• Published in: Acta pharmaceutica Sinica. B Vol. 12; no. 3; pp. 1254 - 1270
• Main Authors: Shan, Shuhua, Niu, Jinping, Yin, Ruopeng, Shi, Jiangying, Zhang, Lizhen, Wu, Caihong, Li, Hanqing, Li, Zhuoyu
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.03.2022; Elsevier
• Subjects: Colorectal cancer; csGRP78; FMBP; Foxtail millet bran; Original; ROS; STAT3; FDA; Colorectal cancer; SPF; EGFR; CETSA; NBD; SBD; ISM; csGRP78; rGRP78; TRAIL; CAC; H&E; STAT3; GRP78; Co-IP; Foxtail millet bran; ER; DCFH-DA; MPs; FMBP; CRC; CDKs; ROS; PD-1; FMBP, peroxidase derived from foxtail millet bran; CDKs, cyclin-dependent kinases; GRP78, glucose-regulated protein 78; SPF, specific pathogen free; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; CRC, colorectal cancer; H&E, hematoxylin & eosin; ROS, reactive oxygen species; CAC, colitis-associated carcinogenesis; DCFH-DA, dichloro-dihydro-fluorescein diacetate; SBD, substrate-binding domain of csGRP78; Co-IP, co-immunoprecipitation; FDA, U.S. Food and Drug Administration; PD-1, programmed death-1; STAT3, signal transducer and activator of transcription 3; NBD, the nucleotide binding domain of csGRP78; EGFR, epidermal growth factor receptor; CETSA, cellular thermal shift assay; ISM, isthmin; MPs, membrane proteins; csGRP78, cell surface glucose-regulated protein 78; rGRP78, recombinant GRP78; ER, endoplasmic reticulum
• ISSN: 2211-3835; 2211-3843
• DOI: 10.1016/j.apsb.2021.10.004

Molecular targeted therapy has become an emerging promising strategy in cancer treatment, and screening the agents targeting at cancer cell specific targets is very desirable for cancer treatment. Our previous study firstly found that a secretory peroxidase of class III derived from foxtail millet bran (FMBP) exhibited excellent targeting anti-colorectal cancer (CRC) activity in vivo and in vitro, whereas its underlying target remains unclear. The highlight of present study focuses on the finding that cell surface glucose-regulated protein 78 (csGRP78) abnormally located on CRC is positively correlated with the anti-CRC effects of FMBP, indicating it serves as a potential target of FMBP against CRC. Further, we demonstrated that the combination of FMBP with the nucleotide binding domain (NBD) of csGRP78 interfered with the downstream activation of signal transducer and activator of transcription 3 (STAT3) in CRC cells, thus promoting the intracellular accumulation of reactive oxygen species (ROS) and cell grown inhibition. These phenomena were further confirmed in nude mice tumor model. Collectively, our study highlights csGRP78 acts as an underlying target of FMBP against CRC, uncovering the clinical potential of FMBP as a targeted agent for CRC in the future. Peroxidase from foxtail millet bran restrains the activation of STAT3 pathway through binding to the nucleotide binding domain of csGRP78 abnormally located on colorectal cancer cells (CRC), and promotes the accumulation of reactive oxygen species, resulting in the retardation of CRC progression. [Display omitted]