PMID- 25500539
OWN - NLM
STAT- MEDLINE
DCOM- 20151124
LR  - 20211203
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Linking)
VI  - 34
IP  - 35
DP  - 2015 Aug 27
TI  - Combined regulation of mTORC1 and lysosomal acidification by GSK-3 suppresses 
      autophagy and contributes to cancer cell growth.
PG  - 4613-23
LID - 10.1038/onc.2014.390 [doi]
AB  - There is controversy over the role of glycogen synthase kinase-3 (GSK-3) in 
      cancer progression. Recent work has implicated GSK-3 in the regulation of 
      mammalian target of rapamycin (mTOR), a known player in malignant transformation. 
      Autophagy, a self-degradation pathway, is inhibited by mTOR and is tightly 
      associated with cell survival and tumor growth. Here we show that GSK-3 
      suppresses autophagy via mTOR complex-1 (mTORC1) and lysosomal regulation. We 
      show that overexpression of GSK-3 isoforms (GSK-3alpha and GSK-3beta) activated mTORC1 
      and suppressed autophagy in MCF-7 human breast cancer cells as indicated by 
      reduced beclin-1 levels and upregulation of sequestosome 1 (p62/SQSTM1). Further, 
      overexpression of GSK-3 increased the number of autophagosomes and inhibited 
      autophagic flux. This activity was directly related to reduced lysosomal 
      acidification triggered by GSK-3 (in which GSK-3beta has a stronger impact). We 
      found that lysosomal acidification is reduced in MCF-7 cells that also exhibit 
      increased levels of autophagosomes and p62/SQSTM1 and increased activity of 
      mTORC1. Subsequently, treating cells with GSK-3 inhibitors restored lysosomal 
      acidification, enhanced autophagic flux and inhibited mTORC1. Furthermore, GSK-3 
      inhibitors inhibited cell proliferation. We provide evidence that GSK3-mediated 
      mTORC1 activity and GSK-3-mediated lysosomal acidification occur via distinct 
      pathways, yet both mTORC1 and lysosomes control cell growth. Finally, we show 
      that GSK-3-reduced lysosomal acidification inhibits endocytic clearance as 
      demonstrated by reduced endocytic degradation of the epidermal growth factor 
      receptor. Taken together, our study places GSK-3 as a key regulator coordinating 
      cellular homeostasis. GSK-3 inhibitors may be useful in targeting mTORC1 and 
      lysosomal acidification for cancer therapy.
FAU - Azoulay-Alfaguter, I
AU  - Azoulay-Alfaguter I
AD  - Department of Human Molecular Genetics and Biochemistry, Sackler School of 
      Medicine, Tel Aviv University, Tel Aviv, Israel.
FAU - Elya, R
AU  - Elya R
AD  - Department of Human Molecular Genetics and Biochemistry, Sackler School of 
      Medicine, Tel Aviv University, Tel Aviv, Israel.
FAU - Avrahami, L
AU  - Avrahami L
AD  - Department of Human Molecular Genetics and Biochemistry, Sackler School of 
      Medicine, Tel Aviv University, Tel Aviv, Israel.
FAU - Katz, A
AU  - Katz A
AD  - Department of Human Molecular Genetics and Biochemistry, Sackler School of 
      Medicine, Tel Aviv University, Tel Aviv, Israel.
FAU - Eldar-Finkelman, H
AU  - Eldar-Finkelman H
AD  - Department of Human Molecular Genetics and Biochemistry, Sackler School of 
      Medicine, Tel Aviv University, Tel Aviv, Israel.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20141215
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (Multiprotein Complexes)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.26 (Glycogen Synthase Kinase 3)
SB  - IM
MH  - *Autophagy
MH  - *Cell Proliferation
MH  - Endocytosis
MH  - Glycogen Synthase Kinase 3/*physiology
MH  - Humans
MH  - Hydrogen-Ion Concentration
MH  - Lysosomes/*enzymology
MH  - MCF-7 Cells
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Multiprotein Complexes/*physiology
MH  - Phagosomes/metabolism
MH  - TOR Serine-Threonine Kinases/*physiology
EDAT- 2014/12/17 06:00
MHDA- 2015/12/15 06:00
CRDT- 2014/12/16 06:00
PHST- 2014/08/31 00:00 [received]
PHST- 2014/10/10 00:00 [revised]
PHST- 2014/10/16 00:00 [accepted]
PHST- 2014/12/16 06:00 [entrez]
PHST- 2014/12/17 06:00 [pubmed]
PHST- 2015/12/15 06:00 [medline]
AID - onc2014390 [pii]
AID - 10.1038/onc.2014.390 [doi]
PST - ppublish
SO  - Oncogene. 2015 Aug 27;34(35):4613-23. doi: 10.1038/onc.2014.390. Epub 2014 Dec 
      15.