Targeting CAMKK2 and SOC Channels as a Novel Therapeutic Approach for Sensitizing Acute Promyelocytic Leukemia Cells to All-Trans Retinoic Acid
Faten Merhi,
Karla Alvarez-Valadez,
Jenifer Trepiana,
Claire Lescoat,
Alexis Groppi,
Jean-William Dupuy,
Pierre Soubeyran,
Guido Kroemer,
Pierre Vacher,
Mojgan Djavaheri-Mergny
Affiliations
Faten Merhi
Institut Bergonié, INSERM U1218, University of Bordeaux, 33000 Bordeaux, France
Karla Alvarez-Valadez
Centre de Recherche des Cordeliers, INSERM UMRS 1138, Sorbonne Université, Université de Paris, Équipe 11 labellisée par la Ligue Contre le Cancer, 75006 Paris, France
Jenifer Trepiana
Institut Bergonié, INSERM U1218, University of Bordeaux, 33000 Bordeaux, France
Claire Lescoat
Centre de Bioinformatique de Bordeaux (CBiB), University of Bordeaux, 33076 Bordeaux, France
Alexis Groppi
Centre de Bioinformatique de Bordeaux (CBiB), University of Bordeaux, 33076 Bordeaux, France
Jean-William Dupuy
University of Bordeaux, Plateforme Protéome, 33076 Bordeaux, France
Pierre Soubeyran
Institut Bergonié, INSERM U1218, University of Bordeaux, 33000 Bordeaux, France
Guido Kroemer
Centre de Recherche des Cordeliers, INSERM UMRS 1138, Sorbonne Université, Université de Paris, Équipe 11 labellisée par la Ligue Contre le Cancer, 75006 Paris, France
Pierre Vacher
PRASE, Platform of Research and Analysis in Environmental Sciences, Doctoral School of Sciences and Technologies, Lebanese University, Hadat Campus, Beirut 1003, Lebanon
Mojgan Djavaheri-Mergny
Centre de Recherche des Cordeliers, INSERM UMRS 1138, Sorbonne Université, Université de Paris, Équipe 11 labellisée par la Ligue Contre le Cancer, 75006 Paris, France
Calcium ions (Ca2+) play important and diverse roles in the regulation of autophagy, cell death and differentiation. Here, we investigated the impact of Ca2+ 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 Ca2+ 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.
