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Protein homeostasis maintained by HOOK1 levels promotes the tumorigenic and stemness properties of ovarian cancer cells through reticulum stress and autophagy.
- Source :
-
Journal of experimental & clinical cancer research : CR [J Exp Clin Cancer Res] 2024 May 29; Vol. 43 (1), pp. 150. Date of Electronic Publication: 2024 May 29. - Publication Year :
- 2024
-
Abstract
- Background: Ovarian cancer has a high mortality rate mainly due to its resistance to currently used therapies. This resistance has been associated with the presence of cancer stem cells (CSCs), interactions with the microenvironment, and intratumoral heterogeneity. Therefore, the search for new therapeutic targets, particularly those targeting CSCs, is important for improving patient prognosis. HOOK1 has been found to be transcriptionally altered in a substantial percentage of ovarian tumors, but its role in tumor initiation and development is still not fully understood.<br />Methods: The downregulation of HOOK1 was performed in ovarian cancer cell lines using CRISPR/Cas9 technology, followed by growth in vitro and in vivo assays. Subsequently, migration (Boyden chamber), cell death (Western-Blot and flow cytometry) and stemness properties (clonal heterogeneity analysis, tumorspheres assay and flow cytometry) of the downregulated cell lines were analysed. To gain insights into the specific mechanisms of action of HOOK1 in ovarian cancer, a proteomic analysis was performed, followed by Western-blot and cytotoxicity assays to confirm the results found within the mass spectrometry. Immunofluorescence staining, Western-blotting and flow cytometry were also employed to finish uncovering the role of HOOK1 in ovarian cancer.<br />Results: In this study, we observed that reducing the levels of HOOK1 in ovarian cancer cells reduced in vitro growth and migration and prevented tumor formation in vivo. Furthermore, HOOK1 reduction led to a decrease in stem-like capabilities in these cells, which, however, did not seem related to the expression of genes traditionally associated with this phenotype. A proteome study, along with other analysis, showed that the downregulation of HOOK1 also induced an increase in endoplasmic reticulum stress levels in these cells. Finally, the decrease in stem-like properties observed in cells with downregulated HOOK1 could be explained by an increase in cell death in the CSC population within the culture due to endoplasmic reticulum stress by the unfolded protein response.<br />Conclusion: HOOK1 contributes to maintaining the tumorigenic and stemness properties of ovarian cancer cells by preserving protein homeostasis and could be considered an alternative therapeutic target, especially in combination with inducers of endoplasmic reticulum or proteotoxic stress such as proteasome inhibitors.<br /> (© 2024. The Author(s).)
- Subjects :
- Animals
Female
Humans
Mice
Cell Line, Tumor
Cell Movement
Cell Proliferation
Microtubule-Associated Proteins metabolism
Microtubule-Associated Proteins genetics
Autophagy
Endoplasmic Reticulum Stress
Neoplastic Stem Cells metabolism
Neoplastic Stem Cells pathology
Ovarian Neoplasms metabolism
Ovarian Neoplasms pathology
Ovarian Neoplasms genetics
Proteostasis genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1756-9966
- Volume :
- 43
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of experimental & clinical cancer research : CR
- Publication Type :
- Academic Journal
- Accession number :
- 38807192
- Full Text :
- https://doi.org/10.1186/s13046-024-03071-2