PMID- 34943872
OWN - NLM
STAT- MEDLINE
DCOM- 20220119
LR  - 20220119
IS  - 2073-4409 (Electronic)
IS  - 2073-4409 (Linking)
VI  - 10
IP  - 12
DP  - 2021 Nov 30
TI  - Targeting CAMKK2 and SOC Channels as a Novel Therapeutic Approach for Sensitizing 
      Acute Promyelocytic Leukemia Cells to All-Trans Retinoic Acid.
LID - 10.3390/cells10123364 [doi]
LID - 3364
AB  - Calcium ions (Ca(2+)) play important and diverse roles in the regulation of 
      autophagy, cell death and differentiation. Here, we investigated the impact of 
      Ca(2+) in regulating acute promyelocytic leukemia (APL) cell fate in response to 
      the anti-cancer agent all-trans retinoic acid (ATRA). We observed that ATRA 
      promotes calcium entry through store-operated calcium (SOC) channels into acute 
      promyelocytic leukemia (APL) cells. This response is associated with changes in 
      the expression profiles of ORAI1 and STIM1, two proteins involved in SOC channels 
      activation, as well as with a significant upregulation of several key proteins 
      associated to calcium signaling. Moreover, ATRA treatment of APL cells led to a 
      significant activation of calcium/calmodulin-dependent protein kinase kinase 2 
      (CAMKK2) and its downstream effector AMP-activated protein kinase (AMPK), linking 
      Ca(2+) signaling to autophagy. Pharmacological inhibition of SOC channels and 
      CAMKK2 enhanced ATRA-induced cell differentiation and death. Altogether, our 
      results unravel an ATRA-elicited signaling pathway that involves SOC 
      channels/CAMKK2 activation, induction of autophagy, inhibition of cellular 
      differentiation and suppression of cell death. We suggest that SOC channels and 
      CAMKK2 may constitute novel drug targets for potentiating the anti-cancer effect 
      of ATRA in APL patients.
FAU - Merhi, Faten
AU  - Merhi F
AD  - Institut Bergonie, INSERM U1218, University of Bordeaux, 33000 Bordeaux, France.
AD  - PRASE, Platform of Research and Analysis in Environmental Sciences, Doctoral 
      School of Sciences and Technologies, Lebanese University, Hadat Campus, Beirut 
      1003, Lebanon.
FAU - Alvarez-Valadez, Karla
AU  - Alvarez-Valadez K
AD  - Centre de Recherche des Cordeliers, INSERM UMRS 1138, Sorbonne Universite, 
      Universite de Paris, Equipe 11 labellisee par la Ligue Contre le Cancer, 75006 
      Paris, France.
AD  - Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 
      Villejuif, France.
FAU - Trepiana, Jenifer
AU  - Trepiana J
AUID- ORCID: 0000-0003-1316-5923
AD  - Institut Bergonie, INSERM U1218, University of Bordeaux, 33000 Bordeaux, France.
FAU - Lescoat, Claire
AU  - Lescoat C
AD  - Centre de Bioinformatique de Bordeaux (CBiB), University of Bordeaux, 33076 
      Bordeaux, France.
FAU - Groppi, Alexis
AU  - Groppi A
AUID- ORCID: 0000-0002-3341-8281
AD  - Centre de Bioinformatique de Bordeaux (CBiB), University of Bordeaux, 33076 
      Bordeaux, France.
AD  - University of Bordeaux, CNRS, IBGC, UMR 5095, 33077 Bordeaux, France.
FAU - Dupuy, Jean-William
AU  - Dupuy JW
AUID- ORCID: 0000-0002-2448-4797
AD  - University of Bordeaux, Plateforme Proteome, 33076 Bordeaux, France.
FAU - Soubeyran, Pierre
AU  - Soubeyran P
AUID- ORCID: 0000-0003-3244-7299
AD  - Institut Bergonie, INSERM U1218, University of Bordeaux, 33000 Bordeaux, France.
FAU - Kroemer, Guido
AU  - Kroemer G
AUID- ORCID: 0000-0002-9334-4405
AD  - Centre de Recherche des Cordeliers, INSERM UMRS 1138, Sorbonne Universite, 
      Universite de Paris, Equipe 11 labellisee par la Ligue Contre le Cancer, 75006 
      Paris, France.
AD  - Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 
      Villejuif, France.
AD  - Pole de Biologie, Hopital Europeen Georges Pompidou, AP-HP, 75015 Paris, France.
FAU - Vacher, Pierre
AU  - Vacher P
AUID- ORCID: 0000-0003-3503-7981
AD  - PRASE, Platform of Research and Analysis in Environmental Sciences, Doctoral 
      School of Sciences and Technologies, Lebanese University, Hadat Campus, Beirut 
      1003, Lebanon.
FAU - Djavaheri-Mergny, Mojgan
AU  - Djavaheri-Mergny M
AUID- ORCID: 0000-0003-4893-6505
AD  - Centre de Recherche des Cordeliers, INSERM UMRS 1138, Sorbonne Universite, 
      Universite de Paris, Equipe 11 labellisee par la Ligue Contre le Cancer, 75006 
      Paris, France.
AD  - Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, 94805 
      Villejuif, France.
LA  - eng
GR  - ANR-18-IDEX-0001./F.M. was supported by a post-doctoral fellowship from the 
      "Aquitaine Regional Council "(to MDM). K.A-V is supported by the Mexican National 
      Council of Science and Technology (CONACYT, funding #757821). This work was 
      supported by funds from the Institut N/
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20211130
PL  - Switzerland
TA  - Cells
JT  - Cells
JID - 101600052
RN  - 0 (Calcium Channels)
RN  - 5688UTC01R (Tretinoin)
RN  - EC 2.7.11.17 (CAMKK2 protein, human)
RN  - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Kinase)
RN  - EC 2.7.4.3 (Adenylate Kinase)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Adenylate Kinase/metabolism
MH  - Autophagy/drug effects
MH  - Calcium/metabolism
MH  - Calcium Channels/*metabolism
MH  - Calcium-Calmodulin-Dependent Protein Kinase Kinase/*metabolism
MH  - Cell Differentiation/drug effects
MH  - Cell Line, Tumor
MH  - Drug Resistance, Neoplasm/drug effects
MH  - Enzyme Activation/drug effects
MH  - Granulocytes/drug effects/metabolism/pathology
MH  - Humans
MH  - Leukemia, Promyelocytic, Acute/*drug therapy/*metabolism
MH  - Tretinoin/pharmacology/*therapeutic use
MH  - Up-Regulation/drug effects
PMC - PMC8699360
OTO - NOTNLM
OT  - AMPK
OT  - ORAI1
OT  - STIM1
OT  - autophagy
OT  - cancer
OT  - cell death
OT  - differentiation
OT  - resistance to therapy
OT  - therapy
COIS- G.K. has been holding research contracts with Daiichi Sankyo, Eleor, Kaleido, 
      Lytix Pharma, PharmaMar, Samsara, Sanofi, Sotio, Vascage and Vasculox/Tioma; is 
      on the Board of Directors of the Bristol Myers Squibb Foundation France; and is a 
      scientific co-founder of everImmune, Samsara Therapeutics and Therafast Bio.
EDAT- 2021/12/25 06:00
MHDA- 2022/01/20 06:00
PMCR- 2021/11/30
CRDT- 2021/12/24 01:03
PHST- 2021/10/06 00:00 [received]
PHST- 2021/11/20 00:00 [revised]
PHST- 2021/11/22 00:00 [accepted]
PHST- 2021/12/24 01:03 [entrez]
PHST- 2021/12/25 06:00 [pubmed]
PHST- 2022/01/20 06:00 [medline]
PHST- 2021/11/30 00:00 [pmc-release]
AID - cells10123364 [pii]
AID - cells-10-03364 [pii]
AID - 10.3390/cells10123364 [doi]
PST - epublish
SO  - Cells. 2021 Nov 30;10(12):3364. doi: 10.3390/cells10123364.