Pharmacological inhibition of Polo-like kinase 1 (PLK1) by BI-2536 decreases
the viability and survival of hamartin and tuberin deficient cells via induction of
apoptosis and attenuation of autophagy |
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Authors: | Matthildi Valianou Andrew M Cox Benjamin Pichette Shannon Hartley Unmesha Roy Paladhi Aristotelis Astrinidis |
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Institution: | 1.Department of Biochemistry and Molecular
Biology; Drexel University College of Medicine; Philadelphia, PA USA;2.Laboratory of Biological Chemistry; Department
of Medicine; School of Health Sciences; University of Ioannina, Greece;3.Department of Immunotherapeutics and
Biotechnology; School of Pharmacy; Texas Tech University Health Sciences
Center; Abilene, TX USA |
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Abstract: | The mechanistic target of rapamycin complex 1 (mTORC1) increases translation, cell size
and angiogenesis, and inhibits autophagy. mTORC1 is negatively regulated by hamartin and
tuberin, the protein products of the tumor suppressors TSC1 and
TSC2 that are mutated in Tuberous Sclerosis Complex (TSC) and sporadic
Lymphangioleiomyomatosis (LAM). Hamartin interacts with the centrosomal and mitotic kinase
polo-like kinase 1 (PLK1). Hamartin and tuberin deficient cells have abnormalities in
centrosome duplication, mitotic progression, and cytokinesis, suggesting that the
hamartin/tuberin heterodimer and mTORC1 signaling are involved in centrosome biology and
mitosis. Here we report that PLK1 protein levels are increased in hamartin and tuberin
deficient cells and LAM patient-derived specimens, and that this increase is
rapamycin-sensitive. Pharmacological inhibition of PLK1 by the small-molecule inhibitor
BI-2536 significantly decreased the viability and clonogenic survival of hamartin and
tuberin deficient cells, which was associated with increased apoptosis. BI-2536 increased
p62, LC3B-I and GFP-LC3 punctae, and inhibited HBSS-induced degradation of p62, suggesting
that PLK1 inhibition attenuates autophagy. Finally, PLK1 inhibition repressed the
expression and protein levels of key autophagy genes and proteins and the protein levels
of Bcl-2 family members, suggesting that PLK1 regulates both autophagic and
apoptotic responses. Taken together, our data point toward a previously unrecognized role
of PLK1 on the survival of cells with mTORC1 hyperactivation, and the potential use of
PLK1 inhibitors as novel therapeutics for tumors with dysregulated mTORC1 signaling,
including TSC and LAM. |
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Keywords: | apoptosis autophagy BI-2536 lymphangioleiomyomatosis mechanistic target of rapamycin polo-like kinase 1 tuberous sclerosis complex |
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