Metformin Induces Apoptosis through AMPK-Dependent Inhibition of UPR Signaling in ALL Lymphoblasts

Gilles M. Leclerc, Guy J. Leclerc, Jeffim N. Kuznetsov, Joanna DeSalvo, Julio Barredo

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

The outcome of patients with resistant phenotypes of acute lymphoblastic leukemia (ALL) or those who relapse remains poor. We investigated the mechanism of cell death induced by metformin in Bp- and T-ALL cell models and primary cells, and show that metformin effectively induces apoptosis in ALL cells. Metformin activated AMPK, down-regulated the unfolded protein response (UPR) demonstrated by significant decrease in the main UPR regulator GRP78, and led to UPR-mediated cell death via up-regulation of the ER stress/UPR cell death mediators IRE1α and CHOP. Using shRNA, we demonstrate that metformin-induced apoptosis is AMPK-dependent since AMPK knock-down rescued ALL cells, which correlated with down-regulation of IRE1α and CHOP and restoration of the UPR/GRP78 function. Additionally rapamycin, a known inhibitor of mTOR-dependent protein synthesis, rescued cells from metformin-induced apoptosis and down-regulated CHOP expression. Finally, metformin induced PIM-2 kinase activity and co-treatment of ALL cells with a PIM-1/2 kinase inhibitor plus metformin synergistically increased cell death, suggesting a buffering role for PIM-2 in metformin's cytotoxicity. Similar synergism was seen with agents targeting Akt in combination with metformin, supporting our original postulate that AMPK and Akt exert opposite regulatory roles on UPR activity in ALL. Taken together, our data indicate that metformin induces ALL cell death by triggering ER and proteotoxic stress and simultaneously down-regulating the physiologic UPR response responsible for effectively buffering proteotoxic stress. Our findings provide evidence for a role of metformin in ALL therapy and support strategies targeting synthetic lethal interactions with Akt and PIM kinases as suitable for future consideration for clinical translation in ALL.

Original languageEnglish
Article numbere74420
JournalPLoS One
Volume8
Issue number8
DOIs
StatePublished - Aug 23 2013

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metformin
unfolded protein response
Unfolded Protein Response
AMP-activated protein kinase
lymphocytic leukemia
AMP-Activated Protein Kinases
Metformin
Precursor Cell Lymphoblastic Leukemia-Lymphoma
apoptosis
Apoptosis
Cell death
Proteins
cell death
Cell Death
phosphotransferases (kinases)
Phosphotransferases
cells
TOR Serine-Threonine Kinases
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
relapse

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Metformin Induces Apoptosis through AMPK-Dependent Inhibition of UPR Signaling in ALL Lymphoblasts. / Leclerc, Gilles M.; Leclerc, Guy J.; Kuznetsov, Jeffim N.; DeSalvo, Joanna; Barredo, Julio.

In: PLoS One, Vol. 8, No. 8, e74420, 23.08.2013.

Research output: Contribution to journalArticle

Leclerc, Gilles M. ; Leclerc, Guy J. ; Kuznetsov, Jeffim N. ; DeSalvo, Joanna ; Barredo, Julio. / Metformin Induces Apoptosis through AMPK-Dependent Inhibition of UPR Signaling in ALL Lymphoblasts. In: PLoS One. 2013 ; Vol. 8, No. 8.
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