1. Role of AMPK and Akt in triple negative breast cancer lung colonization
- Author
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Heidi L. Weiss, B. Mark Evers, Jeremy Johnson, Zeta Chow, Piotr G. Rychahou, and Eun Y. Lee
- Subjects
0301 basic medicine ,Cancer Research ,IHC, Immunohistochemistry ,Lung Neoplasms ,AKT1 ,AKT2 ,Apoptosis ,Triple Negative Breast Neoplasms ,Mice, SCID ,AMP-Activated Protein Kinases ,Mice ,0302 clinical medicine ,Circulating tumor cell ,Akt, Protein kinase B ,Mice, Inbred NOD ,PS, Pencillin-streptomycin ,RPMI, Roswell Park Memorial Institute ,Triple negative breast cancer ,RNA, Small Interfering ,Triple-negative breast cancer ,AMPKα ,Neoplastic Cells, Circulating ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,ER+, Estrogen receptor-positive ,WB, Western blot ,030220 oncology & carcinogenesis ,GFP, Green fluorescent protein ,siRNA, Small interfering RNA ,Female ,RNA Interference ,Signal transduction ,TNBC, Triple negative breast cancer ,Heterocyclic Compounds, 3-Ring ,Signal Transduction ,Original article ,PBS, Phosphate buffered saline ,Biology ,lcsh:RC254-282 ,NSG, NOD-scid IL2Rgammanull ,03 medical and health sciences ,Cell Line, Tumor ,Animals ,Humans ,Neoplasm Invasiveness ,Pyrroles ,Protein kinase B ,Akt ,AMPK ,Organ metastasis ,AMPK, AMP-activated protein kinase ,030104 developmental biology ,Pyrimidines ,Cancer cell ,Cancer research ,FBS, Fetal bovine serum ,Energy Metabolism ,Proto-Oncogene Proteins c-akt - Abstract
Triple negative breast cancer (TNBC) is an aggressive disease with a 5-y relative survival rate of 11% after distant metastasis. To survive the metastatic cascade, tumor cells remodel their signaling pathways by regulating energy production and upregulating survival pathways. AMP-activated protein kinase (AMPK) and Akt regulate energy homeostasis and survival, however, the individual or synergistic role of AMPK and Akt isoforms during lung colonization by TNBC cells is unknown. The purpose of this study was to establish whether targeting Akt, AMPKα or both Akt and AMPKα isoforms in circulating cancer cells can suppress TNBC lung colonization. Transient silencing of Akt1 or Akt2 dramatically decreased metastatic colonization of lungs by inducing apoptosis or inhibiting invasion, respectively. Importantly, transient pharmacologic inhibition of Akt activity with MK-2206 or AZD5363 inhibitors did not prevent colonization of lung tissue by TNBC cells. Knockdown of AMPKα1, AMPKα2, or AMPKα1/2 also had no effect on metastatic colonization of lungs. Taken together, these findings demonstrate that transient decrease in AMPK isoforms expression alone or in combination with Akt1 in circulating tumor cells does not synergistically reduce TNBC metastatic lung colonization. Our results also provide evidence that Akt1 and Akt2 expression serve as a bottleneck that can challenge colonization of lungs by TNBC cells.
- Published
- 2021