SNX10 (sorting nexin 10) inhibits colorectal cancer initiation and progression by controlling autophagic degradation of SRC.

Abstract

The non-receptor tyrosine kinase SRC is a key mediator of cellular protumorigenic signals. SRC is aberrantly over-expressed and activated in more than 80% of colorectal cancer (CRC) patients, therefore regulation of its stability and activity is essential. Here, we report a significant down regulation of SNX10 (sorting nexin 10) in human CRC tissues, which is closely related to tumor differentiation, TNM stage, lymph node metastasis and survival period. SNX10 deficiency in normal and neoplastic colorectal epithelial cells promotes initiation and progression of CRC in mice. SNX10 controls SRC levels by mediating autophagosome-lysosome fusion and SRC recruitment for autophagic degradation. These mechanisms ensure proper controlling of the activities of SRC-STAT3 and SRC-CTNNB1 signaling pathways by up-regulating SNX10 expression under stress conditions. These findings suggest that SNX10 acts as a tumor suppressor in CRC and it could be a potential therapeutic target for future development.Abbreviations: ACTB: actin beta; ATG5: autophagy related 5; ATG12: autophagy related 12; CQ: chloroquine; CRC: colorectal cancer; CTNNB1: catenin beta 1; EBSS: Earle's balanced salt solution; KO: knockout; LAMP1: lysosomal associated membrane protein 1; LAMP2: lysosomal associated membrane protein 2; MAP1LC3: microtubule associated protein 1 light chain 3; MKI67: marker of proliferation Ki-67; mRNA: messenger RNA; PX: phox homology; RT-qPCR: real time quantitative polymerase chain reaction; siRNA: small interfering RNA; SNX10: sorting nexin 10; SQSTM1: sequestosome 1; SRC: SRC proto-oncogene, non-receptor tyrosine kinase; STAT3: signal transducer and activator of transcription 3; WT: wild type.

• Authors: Sulin Zhang, Zhiwen Yang, Weilian Bao, Lixin Liu, Yan You, Xu Wang, Liming Shao, Wei Fu, Xinhui Kou, Weixing Shen, Congmin Yuan, Bin Hu, Wenzhen Dang, Kutty Selva Nandakumar, Hualiang Jiang, Mingyue Zheng, Xiaoyan Shen
• Journal: Autophagy (Autophagy) Vol. 16 Issue 4 Pg. 735-749 (04 2020) ISSN: 1554-8635 [Electronic] United States
• PMID: 31208298 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• MAS1 protein, human
• Microtubule-Associated Proteins
• Proto-Oncogene Mas
• SNX10 protein, human
• SNX10 protein, mouse
• Sorting Nexins

Topics

• Animals
• Autophagy (genetics, physiology)
• Cell Movement (physiology)
• Colorectal Neoplasms (metabolism, pathology)
• Down-Regulation
• Humans
• Lysosomes (metabolism)
• Mice
• Microtubule-Associated Proteins (metabolism)
• Proto-Oncogene Mas
• Sorting Nexins (deficiency, genetics, metabolism)
• Up-Regulation