Tuberous sclerosis complex 1 (TSC1) regulates the inhibition of mammalian target of rapamycin (mTOR), a central promotor of cell growth and proliferation. TSC1 interacts with Polo-like kinase 1 (Plk1). A less well-characterized member of the Polo-like kinase family, Polo-like Kinase 2 (Plk2/Snk) is a direct target for transcriptional regulation by p53. The specific hypothesis is that 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 base this hypothesis on the following observations. Xenograft tumors comprised of Plk2 deficient H460 human lung cancer cells grew larger than control tumors. Plk2 was demonstrated to interact with TSC1. HCT 116 cells transiently over-expressing Plk2 demonstrated decreased phosphorylation of the downstream target of mTOR, ribosomal protein S6 kinase (S6K) during hypoxia. TSC1 levels were elevated in response to Adriamycin, but Plk2 levels did not increase in response to DNA damage after hypoxia. TSC1-deficient mouse embryonic fibroblasts with TSC1 added back demonstrated decreased S6K phosphorylation, which was further decreased when Plk2 was transiently over-expressed providing evidence that Plk2 may play a role in the restraint of mTOR by TSC1. Under normoxia, Plk2 deficient H460 cells demonstrated increased apoptosis in response to CPT-11 but increased resistance to CPT-11 under hypoxia. Tumor xenografts comprised of these Plk2 deficient cells were similarly resistant to CPT-11. An examination of the effects of Plk2-TSC1 interaction on mTOR signaling during hypoxia, DNA damage and tumor progression will enable the development of Plk2 as promising new therapeutic target. This work provides compelling evidence for cross-talk between the p53 and mTOR that may aid the development of cancer therapies targeting these pathways.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 618.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO