Microcolin H, a novel autophagy inducer, exerts potent antitumour activity by targeting PITPα/β

• Published in: Signal transduction and targeted therapy Vol. 8; no. 1; p. 428
• Main Authors: Yang, Hange, Zhang, Xiaowei, Wang, Cong, Zhang, Hailong, Yi, Juan, Wang, Kun, Hou, Yanzhe, Ji, Peihong, Jin, Xiaojie, Li, Chenghao, Zhang, Min, Huang, Shan, Jia, Haoyuan, Hu, Kuan, Mou, Lingyun, Wang, Rui
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.11.2023; Nature Publishing Group
• Subjects: 631/154/555; 631/92/556; 692/4028/67/1059/153; Animal models; Animals; Autophagy; Autophagy - genetics; Cancer Research; Cancer therapies; Cell Biology; Cell death; Cell Line, Tumor; Internal Medicine; Lipid metabolism; Medicine; Medicine & Public Health; Mice; Oncology; Pathology; Phosphatidylinositol; Phosphatidylinositol transfer protein; Phospholipid Transfer Proteins - chemistry; Phospholipid Transfer Proteins - metabolism; Proteomics; Therapeutic targets; Toxicity; Tumor cell lines; Tumors
• ISSN: 2059-3635; 2095-9907; 2059-3635
• DOI: 10.1038/s41392-023-01667-2

The identification of effective drug targets and the development of bioactive molecules are areas of high need in cancer therapy. The phosphatidylinositol transfer protein alpha/beta isoform (PITPα/β) has been reported to play an essential role in integrating phosphoinositide trafficking and lipid metabolism in diverse cellular processes but remains unexplored as a potential target for cancer treatment. Herein, data analysis of clinical cancer samples revealed that PITPα/β expression is closely correlated with the poor prognosis. Target identification by chemical proteomic methods revealed that microcolin H, a naturally occurring marine lipopeptide, directly binds PITPα/β and displays antiproliferative activity on different types of tumour cell lines. Furthermore, we identified that microcolin H treatment increased the conversion of LC3I to LC3II, accompanied by a reduction of the level of p62 in cancer cells, leading to autophagic cell death. Moreover, microcolin H showed preeminent antitumour efficacy in nude mouse subcutaneous tumour models with low toxicity. Our discoveries revealed that by targeting PITPα/β, microcolin H induced autophagic cell death in tumours with efficient anti-proliferating activity, which sheds light on PITPα/β as a promising therapeutic target for cancer treatment.