Tuberous sclerosis complex 1 (TSC1) inhibits
mammalian target of rapamycin (mTOR), a central promotor of cell growth and proliferation. The
protein product of the TSC1 gene,
hamartin (referred to as TSC1) is known to interact with
Polo-like kinase 1 (Plk1) in a cell cycle regulated, phosphorylation-dependent manner. We hypothesized that the p53 target gene, Plk2, is a
tumor suppressor, mediating its
tumor suppressor function through interactions with TSC1 that facilitate TSC1/2 restraint of mTOR under hypoxic stress. We found that human lung
tumor cells deficient in Plk2 grew larger than control
tumors, and that Plk2 interacts with endogenous TSC1
protein. Additionally, C-terminal Plk2-GST fusion
protein bound both TSC1 and TSC2
proteins. TSC1 levels were elevated in response to
Adriamycin and cells transiently overexpressing Plk2 demonstrated decreased phosphorylation of the downstream target of mTOR,
ribosomal protein p70S6
kinase during
hypoxia. Plk2 levels were inversely correlated with cytoplasmic
p70S6K phosphorylation. Plk2 levels did not increase in response to DNA damage (
Adriamycin,
CPT -11) when HCT 116 and H460 cells were exposed to
hypoxia. TSC1-deficient mouse embryonic fibroblasts with TSC1 added back demonstrated decreased S6K phosphorylation, which was further decreased when Plk2 was transiently overexpressed. Interestingly, under normoxia, Plk2 deficient
tumor cells demonstrated increased apoptosis in response to various chemotherapeutic agents including
CPT -11 but increased resistance to apoptotic death after
CPT-11 treatment under
hypoxia, and
tumor xenografts comprised of these Plk2-deficient cells were resistant to
CPT -11. Our results point to a novel Plk2-TSC1 interaction with effects on mTOR signaling during
hypoxia, and
tumor growth that may enable targeting Plk2 signaling in
cancer therapy.