The STRIPAK Complex Regulates Response to Chemotherapy Through p21 and p27

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T1 - The STRIPAK Complex Regulates Response to Chemotherapy Through p21 and p27

AU - Rodriguez-Cupello, Carmen

AU - Dam, Monica

AU - Serini, Laura

AU - Wang, Shan

AU - Lindgren, David

AU - Englund, Emelie

AU - Kjellman, Pontus

AU - Axelson, Håkan

AU - García Mariscal, Alberto

AU - Madsen, Chris

PY - 2020/3/17

Y1 - 2020/3/17

N2 - The STRIPAK complex has been linked to a variety of biological processes taking place during embryogenesis and development, but its role in cancer has only just started to be defined. Here, we expand on previous work indicating a role for the scaffolding protein STRIP1 in cancer cell migration and metastasis. We show that cell cycle arrest and decreased proliferation are seen upon loss of STRIP1 in MDA-MB-231 cells due to the induction of cyclin dependent kinase inhibitors, including p21 and p27. We demonstrate that p21 and p27 induction is observed in a subpopulation of cells having low DNA damage response and that the p21high/γH2AXlow ratio within single cells can be rescued by depleting MST3&4 kinases. While the loss of STRIP1 decreases cell proliferation and tumor growth, cells treated with low dosage of chemotherapeutics in vitro paradoxically escape therapy-induced senescence and begin to proliferate after recovery. This corroborates with already known research on the dual role of p21 and indicates that STRIP1 also plays a contradictory role in breast cancer, suppressing tumor growth, but once treated with chemotherapeutics, allowing for possible recurrence and decreased patient survival.

AB - The STRIPAK complex has been linked to a variety of biological processes taking place during embryogenesis and development, but its role in cancer has only just started to be defined. Here, we expand on previous work indicating a role for the scaffolding protein STRIP1 in cancer cell migration and metastasis. We show that cell cycle arrest and decreased proliferation are seen upon loss of STRIP1 in MDA-MB-231 cells due to the induction of cyclin dependent kinase inhibitors, including p21 and p27. We demonstrate that p21 and p27 induction is observed in a subpopulation of cells having low DNA damage response and that the p21high/γH2AXlow ratio within single cells can be rescued by depleting MST3&4 kinases. While the loss of STRIP1 decreases cell proliferation and tumor growth, cells treated with low dosage of chemotherapeutics in vitro paradoxically escape therapy-induced senescence and begin to proliferate after recovery. This corroborates with already known research on the dual role of p21 and indicates that STRIP1 also plays a contradictory role in breast cancer, suppressing tumor growth, but once treated with chemotherapeutics, allowing for possible recurrence and decreased patient survival.

U2 - 10.3389/fcell.2020.00146

DO - 10.3389/fcell.2020.00146

M3 - Article

C2 - 32258031

VL - 8

JO - Frontiers in cell and developmental biology

JF - Frontiers in cell and developmental biology

SN - 2296-634X

M1 - 146

ER -