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Cell Cycle 11:5, 865-870; March 1, 2012; ? 2012 Landes Bioscience

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Key words: metformin, breast cancer, mitochondria, MHC-I, immunosurveil-lance, HER2

Submitted: 12/15/12

Accepted: 01/03/12

http://m.wendangku.net/doc/2e3303353b3567ec102d8ae6.html/10.4161/cc.11.5.19252 *Correspondence to: Javier A. Menendez; Email: jmenendez@http://m.wendangku.net/doc/2e3303353b3567ec102d8ae6.html; jmenendez@ http://m.wendangku.net/doc/2e3303353b3567ec102d8ae6.html A ctive avoidance by tumor ce lls of

attack and e limination by immune cells is an emerging cancer hallmark that is achie ve d primarily by de cre asing the le ve ls of major histocompatibility com-plex class I (MHC-I) at the cancer cells’ surface. Deficiencies in MHC-I antigen-re stricte d immunosurve illance may be inte rtwine d with an alte re d, Warburg-lik e canc e r c e ll-intrinsic m e tabolism, anothe r e me rging hallmark of cance r that involve s a switch from mitochon-drial re spiration to glycolysis to e ffi-cie ntly support large-scale biosynthe tic programs that are re quire d for active cell proliferation. We recently envisioned that int rv ntion strat gi s aim d at re ve rsing the bioe ne rge tic signature of cancer cells (e.g., the antidiabetic bigua-nide metformin) should correct oncogene (e.g., HER2)-driven MHC-I defects, thus pre ve nting immune e scape of oncoge ne transformants. First, we e xplore d how m tformin tr atm nt impact d mito-chondrial bioge ne sis in culture d bre ast cance r ce lls ove re xpre ssing the me m-brane tyrosine kinase re ce ptor HER2, the be st-characte rize d downre gulator of MHC-I. Metformin exposure was found to dose-dependently increase the expres-sion levels of cytochrome c oxidase I and mitochondrial succinate de hydroge nase, which are encoded by mitochondrial and nucle ar DNA, re spe ctive ly. Se cond, we e xplore d whe the r me tformin-e nhance d mitochondrial bioge ne sis might signifi-cantly alter the MHC-I status in bre ast

Metformin rescues cell surface major histocompatibility complex class I (MHC-I) deficiency caused by oncogenic transformation

Cristina Oliveras-Ferraros,1,2,? Sílvia Cufí,1,2,? Alejandro Vazquez-Martin,1,2 Octavio J. Menendez,1 Joaquim Bosch-Barrera,2,3

Bego?a Martin-Castillo,2,4 Jorge Joven5 and Javier A. Menendez1,2,*

1Translational Research Laboratory; 2Girona Biomedical Research Institute; 3Unit of Clinical Research; Medical Oncology; Catalan Institute of Oncology; Girona; 4Centre de Recerca Biomèdica; Hospital Universitari Sant Joan de Reus; 5Institut d’Investigaciò Sanitària Pere Virgili; Universitat Rovira i Virgili; Reus, Catalonia Spain

?These authors contributed equally to this work.

carcinoma ce lls. MHC-I e xpre ssion, as

assessed by flow cytometry using an anti-

HLA-ABC monoclonal antibody, was

fully re store d (up to ~25-fold upre gula-

tion) in MHC-I-ne gative HER2 ge ne-

amplified carcinoma cells. These findings

may help delineate a previously unrecog-

nize d me chanism through which me t-

formin (and metformin-like drugs) may

e nable a cance r patie nt’s own immune

system to mount an efficient anti-metas-

tasis re sponse that can pre ve nt or de lay

dise ase re curre nce. Re store d antige nic-

ity and immunoge nicity of tumor ce lls

may represent a previously unrecognized

primary mode of action unde rlying the

cancer-preventive effects of metformin.

Defects in major histocompatibility com-

plex class I (MHC-I) antigen presentation

are found in most types of human cancers,

with an incidence ranging from approxi-

mately 30–80% of cases depending on the

tumor type.1,2 While MHC-I defects are

already present in early malignant lesions,

loss or downregulation of MHC-I are

more frequently associated with invasive/

metastatic disease progression and poorer

prognoses in ovarian, colorectal and breast

carcinomas.3-5 Accordingly, MHC-I mol-

ecules are significantly downregulated

in migrating cancer cells in vitro and in

invading cancer cells in vivo,6 and less

differentiated cancer stem cells (CSCs)

seem to be associated with weaker expres-

sion of MHC-I molecules.7 Cumulatively,

these findings strongly suggest that low

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