RNA interference screens discover proteases as synthetic lethal partners of PI3K inhibition in breast cancer cells.
Aminopeptidases
/ genetics
Animals
Breast Neoplasms
/ drug therapy
Cell Line, Tumor
Female
Humans
Mice
Peptide Hydrolases
/ metabolism
Phosphatidylinositol 3-Kinases
/ metabolism
Phosphoinositide-3 Kinase Inhibitors
Proto-Oncogene Proteins c-akt
/ metabolism
RNA Interference
Ubiquitin-Specific Peptidase 7
/ genetics
Breast Cancer
Cancer Degradome
Phosphatidylinositol-3-kinase (PI3K)-Pathway
Proteases
RNA Interference
Journal
Theranostics
ISSN: 1838-7640
Titre abrégé: Theranostics
Pays: Australia
ID NLM: 101552395
Informations de publication
Date de publication:
2022
2022
Historique:
received:
21
10
2021
accepted:
13
04
2022
entrez:
8
6
2022
pubmed:
9
6
2022
medline:
10
6
2022
Statut:
epublish
Résumé
PI3K/mTOR signaling is frequently upregulated in breast cancer making inhibitors of this pathway highly promising anticancer drugs. However, PI3K-inhibitors have a low therapeutic index. Therefore, finding novel combinatory treatment options represents an important step towards clinical implementation of PI3K pathway inhibition in breast cancer therapy. Here, we propose proteases as potential synergistic partners with simultaneous PI3K inhibition in breast cancer cells. We performed mRNA expression studies and unbiased functional genetic synthetic lethality screens by a miR-E based knockdown system targeting all genome-encoded proteases, i.e. the degradome of breast cancer cells. Importantly theses RNA interference screens were done in combination with two PI3K pathway inhibitors. Protease hits were validated in human and murine breast cancer cell lines as well as in non-cancerous cells by viability and growth assays. The degradome-wide genetic screens identified 181 proteases that influenced susceptibility of murine breast cancer cells to low dose PI3K inhibition. Employing independently generated inducible knockdown cell lines we validated 12 protease hits in breast cancer cells. In line with the known tumor promoting function of these proteases we demonstrated Usp7 and Metap2 to be important for murine and human breast cancer cell growth and discovered a role for Metap1 in this context. Most importantly, we demonstrated that Usp7, Metap1 or Metap2 knockdown combined with simultaneous PI3K inhibition resulted in synergistic impairment of murine and human breast cancer cell growth Conclusion: We successfully established proteases as combinatory targets with PI3K inhibition in human and murine breast cancer cells. Usp7, Metap1 and Metap2 are synthetic lethal partners of simultaneous protease/PI3K inhibition, which may refine future breast cancer therapy.
Identifiants
pubmed: 35673573
doi: 10.7150/thno.68299
pii: thnov12p4348
pmc: PMC9169373
doi:
Substances chimiques
Phosphoinositide-3 Kinase Inhibitors
0
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
Peptide Hydrolases
EC 3.4.-
Aminopeptidases
EC 3.4.11.-
METAP1 protein, human
EC 3.4.11.-
USP7 protein, human
EC 3.4.19.12
Ubiquitin-Specific Peptidase 7
EC 3.4.19.12
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4348-4373Informations de copyright
© The author(s).
Déclaration de conflit d'intérêts
Competing Interests: The authors have declared that no competing interest exists.
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