Journal Article

PDK1 promotes tumor growth and metastasis in a spontaneous breast cancer model

Du, J, Chen, S, Chang, Z, Li, D, Dong, Z, Yang, M

2016

Overview

Because malignant cells have altered, usually accelerated, energy consumption, targeting metabolic signaling represents a prevailing strategy for tumor therapy. Phosphoinositide-dependent kinase 1 (PDK1) is a proximal signaling molecule of phosphatidylinositol 3-kinase, which is required for metabolic activation. It is still lacking definitive evidence whether inactivation of PDK1 can overwhelm tumorigenesis in vivo . Herein we revealed that mammary-specific ablation of PDK1 could delay tumor initiation, progression and metastasis in a spontaneous mouse tumor model. We also demonstrated that inducible deletion of PDK1 could noticeably shrink the growing breast tumors. However, a small portion of PDK1-deficient tumorigenic cells eventually established tumor lesions, albeit at a relatively later phase, most likely owing to compensatory upregulation of extracellular signal–regulated kinase 1/2 (Erk1/2) phosphorylation. Consequently, simultaneous inhibition of PDK1 and Erk1/2 impeded the survival of breast cancer cells. Thus we identify PDK1 as a potential therapeutic target for breast cancer, particularly in combination with an Erk1/2 inhibitor.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 1-Phosphatidylinositol 3-kinase / 13/1 / 3-Phosphoinositide-Dependent Protein Kinases - genetics / 3-Phosphoinositide-Dependent Protein Kinases - metabolism / 38/90 / 42/41 / 45/70 / 631/45 / 631/67/1347 / 82/51 / 96/95 / Animals / Apoptosis / Blotting, Western / Breast cancer / Breast Neoplasms - genetics / Breast Neoplasms - metabolism / Breast Neoplasms - pathology / Care and treatment / Cell Biology / Disease Models, Animal / Dosage and administration / Drug therapy / Energy consumption / Extracellular signal-regulated kinase / Extracellular Signal-Regulated MAP Kinases - metabolism / Female / Human Genetics / Humans / Internal Medicine / Kaplan-Meier Estimate / Kinases / Mammary Neoplasms, Animal - genetics / Mammary Neoplasms, Animal - metabolism / Mammary Neoplasms, Animal - pathology / Medicine / Medicine & Public Health / Metabolic activation / Metabolic rate / Metabolism / Metastases / Metastasis / Mice, Knockout / Mice, Transgenic / Microscopy, Confocal / Neoplasm Metastasis / Oncology / original-article / Phosphatidylinositol 3-Kinases - metabolism / Phosphorylation / Protein kinases / Proto-Oncogene Proteins c-akt - metabolism / Rapamycin / Reverse Transcriptase Polymerase Chain Reaction / Signal Transduction / Therapeutic targets / TOR Serine-Threonine Kinases - metabolism / Tumor Burden / Tumorigenesis / Tumors