TY - JOUR
T1 - Metabolic perturbation sensitizes human breast cancer to NK cell-mediated cytotoxicity by increasing the expression of MHC class I chain-related A/B
AU - Fu, Dexue
AU - Geschwind, Jean Francois
AU - Karthikeyan, Swathi
AU - Miller, Eliyahu
AU - Kunjithapatham, Rani
AU - Wang, Zhijun
AU - Ganapathy-Kanniappan, Shanmugasundaram
N1 - Funding Information:
This work was supported by the grant from the United States Department of Defense (award no. W81XWH-11-1-0343), Abdulrahman Abdulmalik Research Fund and Charles Wallace Pratt Research Fund.
Publisher Copyright:
© 2015 Taylor & Francis Group, LLC.
PY - 2015
Y1 - 2015
N2 - Cleavage or shedding of the surface antigen, MHC class I chain-related (MIC) protein (A/B) has been known to be one of the mechanisms by which tumor cells escape host immune surveillance. Thus, any strategy to augment the surface expression of MICA/B could facilitate anticancer immune response. Here, we demonstrate that metabolic perturbation by the glycolytic inhibitor, 3-bromopyruvate (3-BrPA) augments the surface expression of MICA/B in human breast cancer cell lines, MDA-MB-231 and T47D. Data from in vitro studies show that a non-toxic, low-dose of 3-BrPA is sufficient to perturb energy metabolism, as evident by the activation of p-AMPK, p-AKT and p-PI3K. Further, 3-BrPAtreatment also elevated the levels of MICA/B in human breast cancer cell lines. Significantly, 3-BrPA-dependent increase in MICA/B levels also enhanced the sensitivity of cancer cells to natural killer (NK-92MI)-mediated cytotoxicity. In vivo, 3- BrPA-pretreated cells demonstrated greater sensitivity to NK-92MI therapy than their respective controls. The antitumor effect was confirmed by a reduction in tumor size and decreased tumor viability as observed by bioluminescence imaging. Histological examination and TUNEL staining demonstrated that NK-92MI administration promoted apoptosis in 3-BrPA-pretreated cells. Taken together, our data show that targeting energy metabolism could be a novel strategy to enhance the effectiveness of anticancer immunotherapeutics.
AB - Cleavage or shedding of the surface antigen, MHC class I chain-related (MIC) protein (A/B) has been known to be one of the mechanisms by which tumor cells escape host immune surveillance. Thus, any strategy to augment the surface expression of MICA/B could facilitate anticancer immune response. Here, we demonstrate that metabolic perturbation by the glycolytic inhibitor, 3-bromopyruvate (3-BrPA) augments the surface expression of MICA/B in human breast cancer cell lines, MDA-MB-231 and T47D. Data from in vitro studies show that a non-toxic, low-dose of 3-BrPA is sufficient to perturb energy metabolism, as evident by the activation of p-AMPK, p-AKT and p-PI3K. Further, 3-BrPAtreatment also elevated the levels of MICA/B in human breast cancer cell lines. Significantly, 3-BrPA-dependent increase in MICA/B levels also enhanced the sensitivity of cancer cells to natural killer (NK-92MI)-mediated cytotoxicity. In vivo, 3- BrPA-pretreated cells demonstrated greater sensitivity to NK-92MI therapy than their respective controls. The antitumor effect was confirmed by a reduction in tumor size and decreased tumor viability as observed by bioluminescence imaging. Histological examination and TUNEL staining demonstrated that NK-92MI administration promoted apoptosis in 3-BrPA-pretreated cells. Taken together, our data show that targeting energy metabolism could be a novel strategy to enhance the effectiveness of anticancer immunotherapeutics.
KW - Breast cancer
KW - Energy metabolism
KW - Immunotherapy
KW - MICA
KW - NK cells
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U2 - 10.4161/2162402X.2014.991228
DO - 10.4161/2162402X.2014.991228
M3 - Article
C2 - 25949910
AN - SCOPUS:84954563722
SN - 2162-4011
VL - 4
SP - 1
EP - 10
JO - OncoImmunology
JF - OncoImmunology
IS - 3
ER -