Repression of LKB1 by miR-17∼92 Sensitizes MYC-Dependent Lymphoma to Biguanide Treatment

Said Izreig; Alexandra Gariepy; Irem Kaymak; Hannah R. Bridges; Ariel O. Donayo; Gaëlle Bridon; Lisa M. DeCamp; Susan M. Kitchen-Goosen; Daina Avizonis; Ryan D. Sheldon; Rob C. Laister; Mark D. Minden; Nathalie A. Johnson; Thomas F. Duchaine; Marc S. Rudoltz; Sanghee Yoo; Michael N. Pollak; Kelsey S. Williams; Russell G. Jones

doi:10.1016/j.xcrm.2020.100014

Repression of LKB1 by miR-17∼92 Sensitizes MYC-Dependent Lymphoma to Biguanide Treatment

Said Izreig, Alexandra Gariepy, Irem Kaymak, Hannah R. Bridges, Ariel O. Donayo, Gaëlle Bridon, Lisa M. DeCamp, Susan M. Kitchen-Goosen, Daina Avizonis, Ryan D. Sheldon, Rob C. Laister, Mark D. Minden, Nathalie A. Johnson, Thomas F. Duchaine, Marc S. Rudoltz, Sanghee Yoo, Michael N. Pollak, Kelsey S. Williams, Russell G. Jones

Research output: Contribution to journal › Article › peer-review

29 Scopus citations

Abstract

Cancer cells display metabolic plasticity to survive stresses in the tumor microenvironment. Cellular adaptation to energetic stress is coordinated in part by signaling through the liver kinase B1 (LKB1)-AMP-activated protein kinase (AMPK) pathway. Here, we demonstrate that miRNA-mediated silencing of LKB1 confers sensitivity of lymphoma cells to mitochondrial inhibition by biguanides. Using both classic (phenformin) and newly developed (IM156) biguanides, we demonstrate that elevated miR-17∼92 expression in Myc⁺ lymphoma cells promotes increased apoptosis to biguanide treatment in vitro and in vivo. This effect is driven by the miR-17-dependent silencing of LKB1, which reduces AMPK activation in response to complex I inhibition. Mechanistically, biguanide treatment induces metabolic stress in Myc⁺ lymphoma cells by inhibiting TCA cycle metabolism and mitochondrial respiration, exposing metabolic vulnerability. Finally, we demonstrate a direct correlation between miR-17∼92 expression and biguanide sensitivity in human cancer cells. Our results identify miR-17∼92 expression as a potential biomarker for biguanide sensitivity in malignancies.

Original language	English
Article number	100014
Journal	Cell Reports Medicine
Volume	1
Issue number	2
DOIs	https://doi.org/10.1016/j.xcrm.2020.100014
State	Published - 19 May 2020
Externally published	Yes

Keywords

AMPK
LKB1
Myc
OXPHOS inhibitor
biguanide
energy-sensing
lymphoma
metabolic vulnerabilities
microRNA

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10.1016/j.xcrm.2020.100014

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Izreig, S., Gariepy, A., Kaymak, I., Bridges, H. R., Donayo, A. O., Bridon, G., DeCamp, L. M., Kitchen-Goosen, S. M., Avizonis, D., Sheldon, R. D., Laister, R. C., Minden, M. D., Johnson, N. A., Duchaine, T. F., Rudoltz, M. S., Yoo, S., Pollak, M. N., Williams, K. S., & Jones, R. G. (2020). Repression of LKB1 by miR-17∼92 Sensitizes MYC-Dependent Lymphoma to Biguanide Treatment. Cell Reports Medicine, 1(2), Article 100014. https://doi.org/10.1016/j.xcrm.2020.100014

@article{f2c1ecd1aa57442c81ed270c5e53658f,

title = "Repression of LKB1 by miR-17∼92 Sensitizes MYC-Dependent Lymphoma to Biguanide Treatment",

abstract = "Cancer cells display metabolic plasticity to survive stresses in the tumor microenvironment. Cellular adaptation to energetic stress is coordinated in part by signaling through the liver kinase B1 (LKB1)-AMP-activated protein kinase (AMPK) pathway. Here, we demonstrate that miRNA-mediated silencing of LKB1 confers sensitivity of lymphoma cells to mitochondrial inhibition by biguanides. Using both classic (phenformin) and newly developed (IM156) biguanides, we demonstrate that elevated miR-17∼92 expression in Myc+ lymphoma cells promotes increased apoptosis to biguanide treatment in vitro and in vivo. This effect is driven by the miR-17-dependent silencing of LKB1, which reduces AMPK activation in response to complex I inhibition. Mechanistically, biguanide treatment induces metabolic stress in Myc+ lymphoma cells by inhibiting TCA cycle metabolism and mitochondrial respiration, exposing metabolic vulnerability. Finally, we demonstrate a direct correlation between miR-17∼92 expression and biguanide sensitivity in human cancer cells. Our results identify miR-17∼92 expression as a potential biomarker for biguanide sensitivity in malignancies.",

keywords = "AMPK, LKB1, Myc, OXPHOS inhibitor, biguanide, energy-sensing, lymphoma, metabolic vulnerabilities, microRNA",

author = "Said Izreig and Alexandra Gariepy and Irem Kaymak and Bridges, \{Hannah R.\} and Donayo, \{Ariel O.\} and Ga{\"e}lle Bridon and DeCamp, \{Lisa M.\} and Kitchen-Goosen, \{Susan M.\} and Daina Avizonis and Sheldon, \{Ryan D.\} and Laister, \{Rob C.\} and Minden, \{Mark D.\} and Johnson, \{Nathalie A.\} and Duchaine, \{Thomas F.\} and Rudoltz, \{Marc S.\} and Sanghee Yoo and Pollak, \{Michael N.\} and Williams, \{Kelsey S.\} and Jones, \{Russell G.\}",

note = "Publisher Copyright: {\textcopyright} 2020 The Author(s)",

year = "2020",

month = may,

day = "19",

doi = "10.1016/j.xcrm.2020.100014",

language = "English",

volume = "1",

journal = "Cell Reports Medicine",

issn = "2666-3791",

publisher = "Cell Press",

number = "2",

}

Izreig, S, Gariepy, A, Kaymak, I, Bridges, HR, Donayo, AO, Bridon, G, DeCamp, LM, Kitchen-Goosen, SM, Avizonis, D, Sheldon, RD, Laister, RC, Minden, MD, Johnson, NA, Duchaine, TF, Rudoltz, MS, Yoo, S, Pollak, MN, Williams, KS & Jones, RG 2020, 'Repression of LKB1 by miR-17∼92 Sensitizes MYC-Dependent Lymphoma to Biguanide Treatment', Cell Reports Medicine, vol. 1, no. 2, 100014. https://doi.org/10.1016/j.xcrm.2020.100014

TY - JOUR

T1 - Repression of LKB1 by miR-17∼92 Sensitizes MYC-Dependent Lymphoma to Biguanide Treatment

AU - Izreig, Said

AU - Gariepy, Alexandra

AU - Kaymak, Irem

AU - Bridges, Hannah R.

AU - Donayo, Ariel O.

AU - Bridon, Gaëlle

AU - DeCamp, Lisa M.

AU - Kitchen-Goosen, Susan M.

AU - Avizonis, Daina

AU - Sheldon, Ryan D.

AU - Laister, Rob C.

AU - Minden, Mark D.

AU - Johnson, Nathalie A.

AU - Duchaine, Thomas F.

AU - Rudoltz, Marc S.

AU - Yoo, Sanghee

AU - Pollak, Michael N.

AU - Williams, Kelsey S.

AU - Jones, Russell G.

PY - 2020/5/19

Y1 - 2020/5/19

N2 - Cancer cells display metabolic plasticity to survive stresses in the tumor microenvironment. Cellular adaptation to energetic stress is coordinated in part by signaling through the liver kinase B1 (LKB1)-AMP-activated protein kinase (AMPK) pathway. Here, we demonstrate that miRNA-mediated silencing of LKB1 confers sensitivity of lymphoma cells to mitochondrial inhibition by biguanides. Using both classic (phenformin) and newly developed (IM156) biguanides, we demonstrate that elevated miR-17∼92 expression in Myc+ lymphoma cells promotes increased apoptosis to biguanide treatment in vitro and in vivo. This effect is driven by the miR-17-dependent silencing of LKB1, which reduces AMPK activation in response to complex I inhibition. Mechanistically, biguanide treatment induces metabolic stress in Myc+ lymphoma cells by inhibiting TCA cycle metabolism and mitochondrial respiration, exposing metabolic vulnerability. Finally, we demonstrate a direct correlation between miR-17∼92 expression and biguanide sensitivity in human cancer cells. Our results identify miR-17∼92 expression as a potential biomarker for biguanide sensitivity in malignancies.

AB - Cancer cells display metabolic plasticity to survive stresses in the tumor microenvironment. Cellular adaptation to energetic stress is coordinated in part by signaling through the liver kinase B1 (LKB1)-AMP-activated protein kinase (AMPK) pathway. Here, we demonstrate that miRNA-mediated silencing of LKB1 confers sensitivity of lymphoma cells to mitochondrial inhibition by biguanides. Using both classic (phenformin) and newly developed (IM156) biguanides, we demonstrate that elevated miR-17∼92 expression in Myc+ lymphoma cells promotes increased apoptosis to biguanide treatment in vitro and in vivo. This effect is driven by the miR-17-dependent silencing of LKB1, which reduces AMPK activation in response to complex I inhibition. Mechanistically, biguanide treatment induces metabolic stress in Myc+ lymphoma cells by inhibiting TCA cycle metabolism and mitochondrial respiration, exposing metabolic vulnerability. Finally, we demonstrate a direct correlation between miR-17∼92 expression and biguanide sensitivity in human cancer cells. Our results identify miR-17∼92 expression as a potential biomarker for biguanide sensitivity in malignancies.

KW - AMPK

KW - LKB1

KW - Myc

KW - OXPHOS inhibitor

KW - biguanide

KW - energy-sensing

KW - lymphoma

KW - metabolic vulnerabilities

KW - microRNA

UR - https://www.scopus.com/pages/publications/85096519195

U2 - 10.1016/j.xcrm.2020.100014

DO - 10.1016/j.xcrm.2020.100014

M3 - Article

C2 - 32478334

AN - SCOPUS:85096519195

SN - 2666-3791

VL - 1

JO - Cell Reports Medicine

JF - Cell Reports Medicine

IS - 2

M1 - 100014

ER -

Repression of LKB1 by miR-17∼92 Sensitizes MYC-Dependent Lymphoma to Biguanide Treatment

Abstract

Keywords

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