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Targeting PI3K and AMPKα Signaling Alone or in Combination to Enhance Radiosensitivity of Triple Negative Breast Cancer

1
Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40536, USA
2
Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA
3
Department of Surgery, University of Kentucky, Lexington, KY 40536, USA
4
Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington, KY 40536, USA
*
Author to whom correspondence should be addressed.
Cells 2020, 9(5), 1253; https://doi.org/10.3390/cells9051253
Received: 10 April 2020 / Revised: 13 May 2020 / Accepted: 15 May 2020 / Published: 19 May 2020
(This article belongs to the Section Cell Signaling and Regulated Cell Death)
Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype and is characterized by poor survival. Radiotherapy plays an important role in treating TNBC. The purpose of this study was to determine whether inhibiting the AMP-activated protein kinase (AMPK) and phosphatidylinositol 3-kinase (PI3K) pathways alone or in combination potentiates radiotherapy in TNBC. AMPKα1 and AMPKα2 knockdown diminished cyclin D1 expression and induced G1 cell cycle arrest but did not induce apoptosis alone or in combination with radiotherapy. Next, we analyzed the role of PI3K p85α, p85β, p110α, p110β, Akt1, and Akt2 proteins on TNBC cell cycle progression and apoptosis induction. Akt1 and p110α knockdown diminished cyclin D1 expression and induced apoptosis. Silencing Akt1 promoted synergistic apoptosis induction during radiotherapy and further reduced survival after radiation. Treatment with the Akt inhibitor, MK-2206 48 h after radiotherapy decreased Akt1 levels and potentiated radiation-induced apoptosis. Together, our results demonstrate that AMPKα, p110α, and Akt1 promote TNBC proliferation and that Akt1 is a key regulator of radiosensitivity in TNBC. Importantly, combining radiotherapy with the pharmacological inhibition of Akt1 expression is a potentially promising approach for the treatment of TNBC. View Full-Text
Keywords: triple negative breast cancer; radiation; radiosensitivity; AMPK; PI3K triple negative breast cancer; radiation; radiosensitivity; AMPK; PI3K
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MDPI and ACS Style

Johnson, J.; Chow, Z.; Napier, D.; Lee, E.; Weiss, H.L.; Evers, B.M.; Rychahou, P. Targeting PI3K and AMPKα Signaling Alone or in Combination to Enhance Radiosensitivity of Triple Negative Breast Cancer. Cells 2020, 9, 1253.

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