Dataset Information

The 16p13.3 (PDPK1) Genomic Gain in Prostate Cancer: A Potential Role in Disease Progression.

ABSTRACT: BACKGROUND:Prostate cancer (PCa) is a leading cause of cancer death, and distinguishing aggressive from indolent tumors is a major challenge. Identification and characterization of genomic alterations associated with advanced disease can provide new markers of progression and better therapeutic approaches. METHODS:We performed fluorescence in situ hybridization to detect the copy number gain of chromosome 16p13.3 in 75 PCa samples including 10 lymph node (LN) metastases and their matched primary tumors, 9 samples of castration-resistant prostate cancer (CRPC), and 46 additional primary PCa specimens with clinicopathologic parameters. RESULTS:We detected the gain in 5 of 10 LN metastases and 3 of 5 matched primary tumors, 3 of 9 CRPC samples, and 9 of 46 (20%) primary tumors where the 16p13.3 alteration was associated with high Gleason score and elevated preoperative prostate-specific antigen levels. The level of 16p13.3 gain was higher in LN metastasis and CRPC specimens compared to primary PCa. Chromosome mapping revealed the gain spans PDPK1 encoding the 3-phosphoinositide-dependent protein kinase-1 (PDK1). Knockdown of PDK1 in three PCa cell lines reduced migration without affecting growth and re-expressing PDK1 rescued motility. CONCLUSION:Our findings support a prognostic value of the 16p13.3 gain and a role of PDK1 in PCa progression through migration.

SUBMITTER: Choucair KA

PROVIDER: S-EPMC3568696 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Publications

The 16p13.3 (PDPK1) Genomic Gain in Prostate Cancer: A Potential Role in Disease Progression.

Choucair Khalil A KA Guérard Karl-Philippe KP Ejdelman Joshua J Chevalier Simone S Yoshimoto Maisa M Scarlata Eleonora E Fazli Ladan L Sircar Kanishka K Squire Jeremy A JA Brimo Fadi F Cunha Isabela W IW Aprikian Armen A Gleave Martin M Lapointe Jacques J

Translational oncology 20121201 6

<h4>Background</h4>Prostate cancer (PCa) is a leading cause of cancer death, and distinguishing aggressive from indolent tumors is a major challenge. Identification and characterization of genomic alterations associated with advanced disease can provide new markers of progression and better therapeutic approaches.<h4>Methods</h4>We performed fluorescence in situ hybridization to detect the copy number gain of chromosome 16p13.3 in 75 PCa samples including 10 lymph node (LN) metastases and their ...[more]

PMID: 23401739

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Project description:Frequent p53 mutations (mutp53) not only abolish tumor suppressor capacities but confer various gain-of-function (GOF) activities that impacts molecules and pathways now regarded as central for tumor development and progression. Although the complete impact of GOF is still far from being fully understood, the effects on proliferation, migration, metabolic reprogramming, and immune evasion, among others, certainly constitute major driving forces for human tumors harboring them. In this review we discuss major molecular mechanisms driven by mutp53 GOF. We present novel mechanistic insights on their effects over key functional molecules and processes involved in cancer. We analyze new mechanistic insights impacting processes such as immune system evasion, metabolic reprogramming, and stemness. In particular, the increased lipogenic activity through the mevalonate pathway (MVA) and the alteration of metabolic homeostasis due to interactions between mutp53 and AMP-activated protein kinase (AMPK) and Sterol regulatory element-binding protein 1 (SREBP1) that impact anabolic pathways and favor metabolic reprograming. We address, in detail, the impact of mutp53 over metabolic reprogramming and the Warburg effect observed in cancer cells as a consequence, not only of loss-of-function of p53, but rather as an effect of GOF that is crucial for the imbalance between glycolysis and oxidative phosphorylation. Additionally, transcriptional activation of new targets, resulting from interaction of mutp53 with NF-kB, HIF-1α, or SREBP1, are presented and discussed. Finally, we discuss perspectives for targeting molecules and pathways involved in chemo-resistance of tumor cells resulting from mutp53 GOF. We discuss and stress the fact that the status of p53 currently constitutes one of the most relevant criteria to understand the role of autophagy as a survival mechanism in cancer, and propose new therapeutic approaches that could promote the reduction of GOF effects exercised by mutp53 in cancer.

Dataset Information

The 16p13.3 (PDPK1) Genomic Gain in Prostate Cancer: A Potential Role in Disease Progression.

Publications

The 16p13.3 (PDPK1) Genomic Gain in Prostate Cancer: A Potential Role in Disease Progression.

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