PMID- 37939517
OWN - NLM
STAT- MEDLINE
DCOM- 20231205
LR  - 20231205
IS  - 1879-1506 (Electronic)
IS  - 0003-9969 (Linking)
VI  - 157
DP  - 2024 Jan
TI  - Head and neck cancer stem cell maintenance relies on mTOR signaling, specifically 
      involving the mechanistic target of rapamycin complexes 1 and 2 (mTORC1 and 
      mTORC2).
PG  - 105840
LID - S0003-9969(23)00228-5 [pii]
LID - 10.1016/j.archoralbio.2023.105840 [doi]
AB  - OBJECTIVE: Emerging evidence suggests that the modest response of head and neck 
      squamous cell carcinoma (HNSCC) to treatment is associated with cancer stem cells 
      (CSC). However, the signaling pathways that play a role in HNSCC CSC maintenance 
      and therapy response are not well-understood. In this study, we investigate the 
      response of CSCs to phosphatase and tensin homolog (PTEN) modulation and its 
      potential dependency on the mammalian target of rapamycin (mTOR) signaling. 
      DESIGN: PTEN deficiency was stably induced using short hairpin RNA (shRNA). 
      Downregulation of RPTOR/mTORC1 and RICTOR/mTORC2 was achieved using small 
      interfering RNA (siRNA). CSCs were evaluated through tumorsphere formation and 
      were classified into various subtypes: parasphere, merosphere, and holosphere. We 
      investigated the effect of rapamycin on CSC properties in both control and 
      PTEN-deficient HNSCC cells. RESULTS: PTEN deficiency led to an accumulation of 
      CSCs and enhanced a favorable response to rapamycin treatment. The viability of 
      HNSCC CSCs was dependent on mTOR signaling. Deficiencies in both mTORC1 and 
      mTORC2 reduced the number of CSCs. However, CSCs with PTEN deficiency had a 
      greater reliance on mTORC1 signaling. Interestingly, when considering CSC 
      subtypes, a deficiency in mTORC2 led to an increased number of paraspheres in 
      both the control and PTEN-deficient groups. CONCLUSIONS: Loss of PTEN signaling 
      increased the HNSCC CSC population, which can be targeted by rapamycin. However, 
      the mTORC2 deficiency can induce a problematic selection of paraspheres CSCs 
      subtype.
CI  - Copyright (c) 2023 Elsevier Ltd. All rights reserved.
FAU - Almeida, Luciana O
AU  - Almeida LO
AD  - Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, 
      University of Michigan School of Dentistry, Ann Arbor, MI, USA; Department of 
      Basic and Oral Biology, University of Sao Paulo School of Dentistry, Ribeirao 
      Preto, Sao Paulo, Brazil.
FAU - Silva, Luan Cesar
AU  - Silva LC
AD  - Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, 
      University of Michigan School of Dentistry, Ann Arbor, MI, USA; Department of 
      Oral Diagnosis, Piracicaba Dental School, University of Campinas, Piracicaba, Sao 
      Paulo, Brazil.
FAU - Emerick, Carolina
AU  - Emerick C
AD  - Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, 
      University of Michigan School of Dentistry, Ann Arbor, MI, USA; Department of 
      Oral Diagnosis, Piracicaba Dental School, University of Campinas, Piracicaba, Sao 
      Paulo, Brazil.
FAU - Amorim Dos Santos, Juliana
AU  - Amorim Dos Santos J
AD  - Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, 
      University of Michigan School of Dentistry, Ann Arbor, MI, USA.
FAU - Castilho, Rogerio M
AU  - Castilho RM
AD  - Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, 
      University of Michigan School of Dentistry, Ann Arbor, MI, USA.
FAU - Squarize, Cristiane H
AU  - Squarize CH
AD  - Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, 
      University of Michigan School of Dentistry, Ann Arbor, MI, USA. Electronic 
      address: csquariz@umich.edu.
LA  - eng
PT  - Journal Article
DEP - 20231101
PL  - England
TA  - Arch Oral Biol
JT  - Archives of oral biology
JID - 0116711
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - W36ZG6FT64 (Sirolimus)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Humans
MH  - Mechanistic Target of Rapamycin Complex 2/genetics/metabolism
MH  - Mechanistic Target of Rapamycin Complex 1/genetics/metabolism
MH  - *Sirolimus/pharmacology
MH  - Squamous Cell Carcinoma of Head and Neck
MH  - TOR Serine-Threonine Kinases
MH  - *Head and Neck Neoplasms
MH  - Stem Cells/metabolism
OTO - NOTNLM
OT  - Cancer stem cells
OT  - Chemotherapy
OT  - Head and neck tumors
OT  - Target therapy
COIS- Declaration of Competing Interest The authors declare that they have no known 
      competing financial interests or personal relationships that could have appeared 
      to influence the work reported in this paper.
EDAT- 2023/11/09 00:42
MHDA- 2023/12/05 12:43
CRDT- 2023/11/08 18:06
PHST- 2023/07/11 00:00 [received]
PHST- 2023/10/13 00:00 [revised]
PHST- 2023/10/29 00:00 [accepted]
PHST- 2023/12/05 12:43 [medline]
PHST- 2023/11/09 00:42 [pubmed]
PHST- 2023/11/08 18:06 [entrez]
AID - S0003-9969(23)00228-5 [pii]
AID - 10.1016/j.archoralbio.2023.105840 [doi]
PST - ppublish
SO  - Arch Oral Biol. 2024 Jan;157:105840. doi: 10.1016/j.archoralbio.2023.105840. Epub 
      2023 Nov 1.