PMID- 27929731
OWN - NLM
STAT- MEDLINE
DCOM- 20171128
LR  - 20211204
IS  - 1554-8635 (Electronic)
IS  - 1554-8627 (Print)
IS  - 1554-8627 (Linking)
VI  - 13
IP  - 2
DP  - 2017 Feb
TI  - Autophagic homeostasis is required for the pluripotency of cancer stem cells.
PG  - 264-284
LID - 10.1080/15548627.2016.1260808 [doi]
AB  - Pluripotency is an important feature of cancer stem cells (CSCs) that contributes 
      to self-renewal and chemoresistance. The maintenance of pluripotency of CSCs 
      under various pathophysiological conditions requires a complex interaction 
      between various cellular pathways including those involved in homeostasis and 
      energy metabolism. However, the exact mechanisms that maintain the CSC 
      pluripotency remain poorly understood. In this report, using both human and 
      murine models of CSCs, we demonstrate that basal levels of autophagy are required 
      to maintain the pluripotency of CSCs, and that this process is differentially 
      regulated by the rate-limiting enzyme in the NAD(+) synthesis pathway NAMPT 
      (nicotinamide phosphoribosyltransferase) and the transcription factor POU5F1/OCT4 
      (POU class 5 homeobox 1). First, our data show that the pharmacological 
      inhibition and knockdown (K(D)) of NAMPT or the K(D) of POU5F1 in human CSCs 
      significantly decreased the expression of pluripotency markers POU5F1, NANOG 
      (Nanog homeobox) and SOX2 (SRY-box 2), and upregulated the differentiation 
      markers TUBB3 (tubulin beta 3 class III), CSN2 (casein beta), SPP1 (secreted 
      phosphoprotein 1), GATA6 (GATA binding protein 6), T (T brachyury transcription 
      factor) and CDX2 (caudal type homeobox 2). Interestingly, these 
      pluripotency-regulating effects of NAMPT and POU5F1 were accompanied by 
      contrasting levels of autophagy, wherein NAMPT K(D) promoted while POU5F1 K(D) 
      inhibited the autophagy machinery. Most importantly, any deviation from the basal 
      level of autophagy, either increase (via rapamycin, serum starvation or 
      Tat-beclin 1 [Tat-BECN1] peptide) or decrease (via ATG7 or ATG12 K(D)), strongly 
      decreased the pluripotency and promoted the differentiation and/or senescence of 
      CSCs. Collectively, these results uncover the link between the NAD(+) 
      biosynthesis pathway, CSC transcription factor POU5F1 and pluripotency, and 
      further identify autophagy as a novel regulator of pluripotency of CSCs.
FAU - Sharif, Tanveer
AU  - Sharif T
AD  - a Department of Microbiology and Immunology , Dalhousie University , Halifax , 
      Nova Scotia , Canada.
FAU - Martell, Emma
AU  - Martell E
AD  - a Department of Microbiology and Immunology , Dalhousie University , Halifax , 
      Nova Scotia , Canada.
FAU - Dai, Cathleen
AU  - Dai C
AD  - a Department of Microbiology and Immunology , Dalhousie University , Halifax , 
      Nova Scotia , Canada.
FAU - Kennedy, Barry E
AU  - Kennedy BE
AD  - a Department of Microbiology and Immunology , Dalhousie University , Halifax , 
      Nova Scotia , Canada.
FAU - Murphy, Patrick
AU  - Murphy P
AD  - a Department of Microbiology and Immunology , Dalhousie University , Halifax , 
      Nova Scotia , Canada.
FAU - Clements, Derek R
AU  - Clements DR
AD  - b Department of Pathology , Dalhousie University , Halifax , Nova Scotia , 
      Canada.
FAU - Kim, Youra
AU  - Kim Y
AD  - b Department of Pathology , Dalhousie University , Halifax , Nova Scotia , 
      Canada.
FAU - Lee, Patrick W K
AU  - Lee PW
AD  - a Department of Microbiology and Immunology , Dalhousie University , Halifax , 
      Nova Scotia , Canada.
AD  - b Department of Pathology , Dalhousie University , Halifax , Nova Scotia , 
      Canada.
FAU - Gujar, Shashi A
AU  - Gujar SA
AD  - a Department of Microbiology and Immunology , Dalhousie University , Halifax , 
      Nova Scotia , Canada.
AD  - b Department of Pathology , Dalhousie University , Halifax , Nova Scotia , 
      Canada.
AD  - c Centre for Innovative and Collaborative Health Services Research, Quality and 
      System Performance, IWK Health Centre , Halifax , Nova Scotia , Canada.
LA  - eng
PT  - Journal Article
DEP - 20161208
PL  - United States
TA  - Autophagy
JT  - Autophagy
JID - 101265188
RN  - 0 (Beclin-1)
RN  - 0 (Cytokines)
RN  - 0 (Octamer Transcription Factor-3)
RN  - 0 (POU5F1 protein, human)
RN  - 80168379AG (Doxorubicin)
RN  - EC 2.4.2.12 (Nicotinamide Phosphoribosyltransferase)
RN  - EC 2.4.2.12 (nicotinamide phosphoribosyltransferase, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.1.3.67 (PTEN Phosphohydrolase)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - *Autophagy/drug effects
MH  - Beclin-1/metabolism
MH  - Cell Differentiation/drug effects
MH  - Cell Proliferation/drug effects
MH  - Cell Survival/drug effects
MH  - Cellular Senescence/drug effects
MH  - Cytokines/antagonists & inhibitors/metabolism
MH  - Doxorubicin/pharmacology
MH  - *Homeostasis/drug effects
MH  - Mice
MH  - Models, Biological
MH  - Neoplastic Stem Cells/drug effects/enzymology/*pathology
MH  - Nicotinamide Phosphoribosyltransferase/antagonists & inhibitors/metabolism
MH  - Octamer Transcription Factor-3/metabolism
MH  - PTEN Phosphohydrolase/metabolism
MH  - Phosphorylation/drug effects
MH  - Pluripotent Stem Cells/drug effects/*pathology
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Signal Transduction
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases/metabolism
PMC - PMC5324853
OTO - NOTNLM
OT  - POU5F1/Oct4
OT  - autophagy
OT  - cancer stem cells
OT  - differentiation
OT  - pluripotency
OT  - senescence
EDAT- 2016/12/09 06:00
MHDA- 2017/11/29 06:00
PMCR- 2017/12/08
CRDT- 2016/12/09 06:00
PHST- 2016/12/09 06:00 [pubmed]
PHST- 2017/11/29 06:00 [medline]
PHST- 2016/12/09 06:00 [entrez]
PHST- 2017/12/08 00:00 [pmc-release]
AID - 1260808 [pii]
AID - 10.1080/15548627.2016.1260808 [doi]
PST - ppublish
SO  - Autophagy. 2017 Feb;13(2):264-284. doi: 10.1080/15548627.2016.1260808. Epub 2016 
      Dec 8.