التفاصيل البيبلوغرافية
| العنوان: |
Deubiquitinase USP9X loss sensitizes renal cancer cells to mTOR inhibition. |
| المؤلفون: |
Roldán‐Romero, Juan M., Valdivia, Carlos, Santos, Maria, Lanillos, Javier, Maroto, Pablo, Anguera, Georgia, Calsina, Bruna, Martinez‐Montes, Angel, Monteagudo, María, Mellid, Sara, Leandro‐García, Luis J., Montero‐Conde, Cristina, Cascón, Alberto, Roncador, Giovanna, Coloma, Javier, Robledo, Mercedes, Rodriguez‐Antona, Cristina |
| المصدر: |
International Journal of Cancer; Sep2023, Vol. 153 Issue 6, p1300-1312, 13p |
| مصطلحات موضوعية: |
RENAL cancer, BORTEZOMIB, RAPAMYCIN, CANCER cells, DRUG resistance in cancer cells, RENAL cell carcinoma, MTOR inhibitors |
| مستخلص: |
Mammalian target of rapamycin (mTOR) is a central regulator of mammalian metabolism and physiology. Aberrant hyperactivation of the mTOR pathway promotes tumor growth and metastasis, and can also promote tumor resistance to chemotherapy and cancer drugs; this makes mTOR an attractive cancer therapeutic target. mTOR inhibitors have been approved to treat cancer; however, the mechanisms underlying drug sensitivity remain poorly understood. Here, whole exome sequencing of three chromophobe renal cell carcinoma (chRCC) patients with exceptional mTOR inhibitor sensitivity revealed that all three patients shared somatic mutations in the deubiquitinase gene USP9X. The clonal characteristics of the mutations, which were amassed by studying multiple patients' primary and metastatic samples from various years, together with the low USP9X mutation rate in unselected chRCC series, reinforced a causal link between USP9X and mTOR inhibitor sensitivity. Rapamycin treatment of USP9X‐depleted HeLa and renal cancer 786‐O cells, along with the pharmacological inhibition of USP9X, confirmed that this protein plays a role in patients' sensitivity to mTOR inhibitors. USP9X was not found to exert a direct effect on mTORC1, but subsequent ubiquitylome analyses identified p62 as a direct USP9X target. Increased p62 ubiquitination and the augmented rapamycin effect upon bortezomib treatment, together with the results of p62 and LC3 immunofluorescence assays, suggested that dysregulated autophagy in USP9X‐depleted cells can have a synergistic effect with mTOR inhibitors. In summary, we show that USP9X constitutes a potential novel marker of sensitivity to mTOR inhibitors in chRCC patients, and represents a clinical strategy for increasing the sensitivity to these drugs. [ABSTRACT FROM AUTHOR] |
|
Copyright of International Journal of Cancer is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) |
| قاعدة البيانات: |
Complementary Index |
