Expression of TBX2 promotes anchorage-independent growth and survival in the p53-negative SW13 adrenocortical carcinoma.
The transcriptional regulator TBX2 is genetically amplified in several cancers and has, in addition, important roles in development. In carcinogenesis, TBX2 regulates the cell cycle by suppressing the expression of cyclin-dependent kinase (CDK) inhibitors and destabilizes p53 by suppressing expression of ARF. In embryogenesis, however, TBX2 appears to act independently of the cell cycle or p53 and is regulated by growth factors. Tumorigenic functions of TBX2 that are independent of p53 or cell cycle regulation remain poorly understood. Here we used SW13 carcinoma cells which express inactive p53 and have no detectable p16 or p21 CDK-inhibitors as a model to study these functions. Expression of TBX2 in SW13 cells had no effect on the cell cycle but promoted anchorage-independence and increased resistance to apoptotic stimuli including UV-irradiation, the cytotoxic drug doxorubicin and lethal endoplasmic-reticulum stress. This is a cell type-dependent effect as TBX2 overexpression in PANC1 pancreatic cancer cells which are p53-negative has no effect on colony formation or survival after irradiation. Mechanistically, in SW13 cells, TBX2 overexpression strongly reduced the activation of caspase 3, 8 and 9 following UV-irradiation but without altering the expression of the corresponding procaspases. There were, however, dramatic and specific decreases in the expression of procaspases 1 and 4. The expression of the inhibitor of apoptosis, cIAP2/BIRC3, increased in TBX2-overexpressing cells. TBX2 was upregulated in a PI3K-dependent manner by growth factors that are tumorigenic for SW13. Inhibition of Akt phosphorylation abrogates upregulation of TBX2 by FGF-4. Our findings identify TBX2 as a cell type-dependent survival factor under a p53-negative background, and are indicative of a potentially wider role for TBX2 in carcinogenesis than hitherto described.
Ismail
Amin
A
Endocrine Research Laboratory, Division of Experimental Medicine, McGill University Health Center, Royal Victoria Hospital, Room L2.05, Montreal, QC, Canada H3A 1A1. Electronic address: amin.ismail@mcgill.ca.
Bateman
Andrew
A
Endocrine Research Laboratory, Division of Experimental Medicine, McGill University Health Center, Royal Victoria Hospital, Room L2.05, Montreal, QC, Canada H3A 1A1. Electronic address: andrew.bateman@muhc.mcgill.ca.
D000306:Adrenal Cortex Neoplasms / Q000473:pathology*; D018268:Adrenocortical Carcinoma / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004317:Doxorubicin / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D020825:T-Box Domain Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
C097348:T-Box Domain Protein 2; D020825:T-Box Domain Proteins; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin; D019869:Phosphatidylinositol 3-Kinases