TY - JOUR
T1 - CDC25B partners with PP2A to induce AMPK activation and tumor suppression in triple negative breast cancer
AU - Cairns, Junmei
AU - Ly, Reynold C.
AU - Niu, Nifang
AU - Kalari, Krishna R.
AU - Carlson, Erin E.
AU - Wang, Liewei
N1 - Publisher Copyright:
© 2020 The Author(s) 2020. Published by Oxford University Press on behalf of NAR Cancer.
PY - 2020/12/1
Y1 - 2020/12/1
N2 - Cell division cycle 25 (CDC25) dual specificity phosphatases positively regulate the cell cycle by activating cyclin-dependent kinase/cyclin complexes. Here, we demonstrate that in addition to its role in cell cycle regulation, CDC25B functions as a regulator of protein phosphatase 2A (PP2A), a major cellular Ser/Thr phosphatase, through its direct interaction with PP2A catalytic subunit. Importantly, CDC25B alters the regulation of AMP-activated protein kinase signaling (AMPK) by PP2A, increasing AMPK activity by inhibiting PP2A to dephosphorylate AMPK. CDC25B depletion leads to metformin resistance by inhibiting metformin-induced AMPK activation. Furthermore, dual inhibition of CDC25B and PP2A further inhibits growth of 3D organoids isolated from patient derived xenograft model of breast cancer compared to CDC25B inhibition alone. Our study identifies CDC25B as a regulator of PP2A, and uncovers a mechanism of controlling the activity of a key energy metabolism marker, AMPK.
AB - Cell division cycle 25 (CDC25) dual specificity phosphatases positively regulate the cell cycle by activating cyclin-dependent kinase/cyclin complexes. Here, we demonstrate that in addition to its role in cell cycle regulation, CDC25B functions as a regulator of protein phosphatase 2A (PP2A), a major cellular Ser/Thr phosphatase, through its direct interaction with PP2A catalytic subunit. Importantly, CDC25B alters the regulation of AMP-activated protein kinase signaling (AMPK) by PP2A, increasing AMPK activity by inhibiting PP2A to dephosphorylate AMPK. CDC25B depletion leads to metformin resistance by inhibiting metformin-induced AMPK activation. Furthermore, dual inhibition of CDC25B and PP2A further inhibits growth of 3D organoids isolated from patient derived xenograft model of breast cancer compared to CDC25B inhibition alone. Our study identifies CDC25B as a regulator of PP2A, and uncovers a mechanism of controlling the activity of a key energy metabolism marker, AMPK.
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U2 - 10.1093/narcan/zcaa039
DO - 10.1093/narcan/zcaa039
M3 - Article
AN - SCOPUS:85114171970
SN - 2632-8674
VL - 2
JO - NAR Cancer
JF - NAR Cancer
IS - 4
ER -