The IL-6R and Bmi-1 axis controls self-renewal and chemoresistance of head and neck cancer stem cells.
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
23 10 2021
23 10 2021
Historique:
received:
08
06
2021
accepted:
06
10
2021
revised:
28
09
2021
entrez:
24
10
2021
pubmed:
25
10
2021
medline:
19
2
2022
Statut:
epublish
Résumé
Despite major progress in elucidating the pathobiology of head and neck squamous cell carcinoma (HNSCC), the high frequency of disease relapse correlates with unacceptably deficient patient survival. We previously showed that cancer stem-like cells (CSCs) drive tumorigenesis and progression of HNSCC. Although CSCs constitute only 2-5% of total tumor cells, CSCs contribute to tumor progression by virtue of their high tumorigenic potential and their resistance to chemo-, radio-, and immunotherapy. Not only are CSCs resistant to therapy, but cytotoxic agents actually enhance cancer stemness by activating transcription of pluripotency factors and by inducing expression of Bmi-1, a master regulator of stem cell self-renewal. We hypothesized therapeutic inhibition of interleukin-6 receptor (IL-6R) suppresses Bmi-1 to overcome intrinsic chemoresistance of CSCs. We observed that high Bmi-1 expression correlates with decreased (p = 0.04) recurrence-free survival time in HNSCC patients (n = 216). Blockade of IL-6R by lentiviral knockdown or pharmacologic inhibition with a humanized monoclonal antibody (Tocilizumab) is sufficient to inhibit Bmi-1 expression, secondary sphere formation, and to decrease the CSC fraction even in Cisplatin-resistant HNSCC cells. IL-6R inhibition with Tocilizumab abrogates Cisplatin-mediated increase in CSC fraction and induction of Bmi-1 in patient-derived xenograft (PDX) models of HNSCC. Notably, Tocilizumab inhibits Bmi-1 and suppresses growth of xenograft tumors generated with Cisplatin-resistant HNSCC cells. Altogether, these studies demonstrate that therapeutic blockade of IL-6R suppresses Bmi-1 function and inhibits cancer stemness. These results suggest therapeutic inhibition of IL-6R might be a viable strategy to overcome the CSC-mediated chemoresistance typically observed in HNSCC patients.
Identifiants
pubmed: 34689150
doi: 10.1038/s41419-021-04268-5
pii: 10.1038/s41419-021-04268-5
pmc: PMC8542035
doi:
Substances chimiques
Bmi1 protein, mouse
0
Il6ra protein, mouse
0
Proto-Oncogene Proteins
0
Receptors, Interleukin-6
0
Polycomb Repressive Complex 1
EC 2.3.2.27
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
988Subventions
Organisme : NIDCR NIH HHS
ID : F30 DE029097
Pays : United States
Organisme : NIDCR NIH HHS
ID : K08 DE026500
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA097248
Pays : United States
Organisme : NIDCR NIH HHS
ID : R01 DE021139
Pays : United States
Informations de copyright
© 2021. The Author(s).
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