期刊
CANCER BIOLOGY & THERAPY
卷 12, 期 10, 页码 924-938出版社
TAYLOR & FRANCIS INC
DOI: 10.4161/cbt.12.10.17780
关键词
drug resistance; tamoxifen; metformin; tumor stroma; microenvironment; Warburg Effect; aerobic glycolysis; mitochondrial oxidative phosphorylation; TIGAR; glucose uptake; oxidative stress; reactive oxygen species (ROS); cancer associated fibroblasts
类别
资金
- NIH/NCI [R01-CA-080250, R01-CA-098779, R01-CA-120876, R01-AR-055660, R01-CA-70896, R01-CA-75503, R01-CA-86072, R01-CA-107382]
- Susan G. Komen Breast Cancer Foundation
- Breast Cancer Alliance, Inc.
- Susan G. Komen Career Catalyst Grant
- W.W. Smith Charitable Trust
- Breast Cancer Alliance (BCA)
- American Cancer Society (ACS)
- Margaret Q. Landenberger Research Foundation
- Dr. Ralph and Marian C. Falk Medical Research Trust
- NIH/NCI Cancer Center [P30-CA-56036]
- Pennsylvania Department of Health
- Breakthrough Breast Cancer in the UK
- European Research Council
Here, we show that tamoxifen resistance is induced by cancer-associated fibroblasts (CAFs). Coculture of estrogen receptor positive (ER+) MCF7 cells with fibroblasts induces tamoxifen and fulvestrant resistance with 4.4 and 2.5-fold reductions, respectively, in apoptosis compared with homotypic MCF7 cell cultures. Treatment of MCF7 cells cultured alone with high-energy mitochondrial fuels (L-lactate or ketone bodies) is sufficient to confer tamoxifen resistance, mimicking the effects of coculture with fibroblasts. To further demonstrate that epithelial cancer cell mitochondrial activity is the origin of tamoxifen resistance, we employed complementary pharmacological and genetic approaches. First, we studied the effects of two mitochondrial poisons, namely metformin and arsenic trioxide (ATO), on fibroblast-induced tamoxifen resistance. We show here that treatment with metformin or ATO overcomes fibroblast-induced tamoxifen resistance in MCF7 cells. Treatment with the combination of tamoxifen plus metformin or ATO leads to increases in glucose uptake in MCF7 cells, reflecting metabolic uncoupling between epithelial cancer cells and fibroblasts. In coculture, tamoxifen induces the upregulation of TIGAR (TP53-induced glycolysis and apoptosis regulator), a p53 regulated gene that simultaneously inhibits glycolysis, autophagy and apoptosis and reduces ROS generation, thereby promoting oxidative mitochondrial metabolism. To genetically mimic the effects of coculture, we next recombinantly overexpressed TIGAR in MCF7 cells. Remarkably, TIGAR overexpression protects epithelial cancer cells from tamoxifen-induced apoptosis, providing genetic evidence that increased mitochondrial function confers tamoxifen resistance. Finally, CAFs also protect MCF7 cells against apoptosis induced by other anticancer agents, such as the topoisomerase inhibitor doxorubicin (adriamycin) and the PARP-1 inhibitor ABT-888. These results suggest that the tumor microenvironment may be a general mechanism for conferring drug resistance. In summary, we have discovered that mitochondrial activity in epithelial cancer cells drives tamoxifen resistance in breast cancer and that mitochondrial poisons are able to re-sensitize these cancer cells to tamoxifen. In this context, TIGAR may be a key druggable target for preventing drug resistance in cancer cells, as it protects cancer cells against the onset of stress-induced mitochondrial dys-function and aerobic glycolysis.
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