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A peptide interfering with the dimerization of oncogenic KITENIN protein and its stability suppresses colorectal tumour progression.
- Source :
-
Clinical and translational medicine [Clin Transl Med] 2022 Jul; Vol. 12 (7), pp. e871. - Publication Year :
- 2022
-
Abstract
- The stability of a protein, as well as its function and versatility, can be enhanced through oligomerization. KITENIN (KAI1 C-terminal interacting tetraspanin) is known to promote the malignant progression of colorectal cancer (CRC). How KITENIN maintains its structural integrity and stability are largely unknown, however. Here we investigated the mechanisms regulating the stability of KITENIN with the aim of developing therapeutics blocking its oncogenic functions. We found that KITENIN formed a homo-oligomeric complex and that the intracellular C-terminal domain (KITENIN-CTD) was needed for this oligomerization. Expression of the KITENIN-CTD alone interfered with the formation of the KITENIN homodimer, and the amino acid sequence from 463 to 471 within the KITENIN-CTD was the most effective. This sequence coupled with a cell-penetrating peptide was named a KITENIN dimerization-interfering peptide (KDIP). We next studied the mechanisms by which KDIP affected the stability of KITENIN. The KITENIN-interacting protein myosin-X (Myo10), which has oncogenic activity in several cancers, functioned as an effector to stabilize the KITENIN homodimer in the cis formation. Treatment with KDIP resulted in the disintegration of the homodimer via downregulation of Myo10, which led to increased binding of RACK1 to the exposed RACK1-interacting motif (463-471 aa), and subsequent autophagy-dependent degradation of KITENIN and reduced CRC cell invasion. Intravenous injection of KDIP significantly reduced the tumour burden in a syngeneic mouse tumour model and colorectal liver metastasis in an intrasplenic hepatic metastasis model. Collectively, our present results provide a new cancer therapeutic peptide for blocking colorectal liver metastasis, which acts by inducing the downregulation of Myo10 and specifically targeting the stability of the oncogenic KITENIN protein.<br /> (© 2022 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)
- Subjects :
- Animals
Carrier Proteins metabolism
Cell Line, Tumor
Dimerization
Liver Neoplasms, Experimental metabolism
Liver Neoplasms, Experimental secondary
Mice
Myosins chemistry
Myosins metabolism
Oncogene Proteins chemistry
Oncogene Proteins metabolism
Protein Stability drug effects
Colorectal Neoplasms drug therapy
Colorectal Neoplasms metabolism
Colorectal Neoplasms pathology
Membrane Proteins chemistry
Membrane Proteins metabolism
Peptides pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 2001-1326
- Volume :
- 12
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Clinical and translational medicine
- Publication Type :
- Academic Journal
- Accession number :
- 35853101
- Full Text :
- https://doi.org/10.1002/ctm2.871