The Par-4/PTEN connection in tumor suppression.
Tumor suppressors function in a coordinated regulatory network, and their inactivation is a key step in carcinogenesis. The tumor suppressor Par-4 is a novel integral player in the PTEN network. Thus, Par-4 is absent in a high percentage of human prostate carcinomas, and its loss is concomitantly associated with PTEN loss. Genetic ablation of Par-4 induces fully invasive prostate carcinomas in PTEN-heterozygous mice. In contrast, Par-4 deficiency alone, like PTEN heterozygosis, results in lesions that are unable to progress beyond the benign neoplastic stage known as PIN. At this PIN transition, the mutual induction of Par-4 and PTEN is an additional regulatory step in preventing cancer progression. Par-4 deficiency cooperates with PTEN haploinsufficiency in prostate cancer initiation and progression and their simultaneous inactivation, in addition to enhancing Akt activation, sets in motion a unique mechanism involving the synergistic activation of NFkappaB. These results suggest that the concurrent interruption of complementary signaling pathways targeting PI3K/Akt and NFkappaB activation could provide new and effective strategies for cancer therapy.
Diaz-Meco
Maria T
MT
Department of Cancer and Cell Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA. maria.diazmeco@uc.edu
Abu-Baker
Shadi
S
D000818:Animals; D006801:Humans; D008297:Male; D051379:Mice; D008954:Models, Biological; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D018179:Receptors, Thrombin / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction
D018179:Receptors, Thrombin; D051059:PTEN Phosphohydrolase; C112908:protease-activated receptor 4