Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2009 Aug 15;8(16):2518-22.
doi: 10.4161/cc.8.16.9384. Epub 2009 Aug 29.

The Par-4/PTEN connection in tumor suppression

Maria T Diaz-Meco  1 , Shadi Abu-Baker
Affiliations
Review

The Par-4/PTEN connection in tumor suppression

Maria T Diaz-Meco et al. Cell Cycle. .

Abstract

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.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Cooperation of Par-4 deficiency and PTEN haploinsufficiency in prostate cancer progression. Par-4 loss cooperates with PTEN heterozygosity to promote invasive prostate carcinoma. The simultaneous inactivation of Par-4 and PTEN enhances Akt and leads to a synergistic stimulation of the NFκB pathway. This sets in motion complementary signals regulating cell growth, cell survival, inflammation and angiogenesis that collaborate in prostate cancer progression. It is not known whether Akt is able to directly impinge on the NFκB pathway in this system.
Figure 2
Figure 2
Increased levels of PTEN in Par-4 KO prostates. (A) Immunostaining showing increased PTEN levels in prostate epithelial cells in Par-4 KO mice. (B) PTEN mRNA levels are also induced upon Par-4 deficiency, as measured by QRT-PCR. n = 4 mice per genotype. *p < 0.02.
Figure 3
Figure 3
Induction of Par-4 in PTEN+/− prostates. (A) Immunostaining showing increased Par-4 levels in prostate epithelial cells of the anterior (upper) and dorsal (lower) prostate lobes in PTEN+/− mice. (B) Induction of Par-4 mRNA levels in dorsal prostates of PTEN+/− mice, as measured by QRT-PCR. n = 4 mice per genotype. *p < 0.01.
See this image and copyright information in PMC

References

    1. Isaacs W, De Marzo A, Nelson WG. Focus on prostate cancer. Cancer Cell. 2002;2:113–6. - PubMed
    1. Feldman BJ, Feldman D. The development of androgen-independent prostate cancer. Nat Rev Cancer. 2001;1:34–45. - PubMed
    1. Vogelstein B, Kinzler KW. Cancer genes and the pathways they control. Nat Med. 2004;10:789–99. - PubMed
    1. Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast and prostate cancer. Science. 1997;275:1943–7. - PubMed
    1. Steck PA, Pershouse MA, Jasser SA, Yung WK, Lin H, Ligon AH, et al. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23. 3 that is mutated in multiple advanced cancers. Nat Genet. 1997;15:356–62. - PubMed

Publication types

Substances