ABSTRACT
Exosomes, a subgroup of extracellular vesicles (EVs), have been shown to serve as a conduit for the exchange of genetic information between cells. Exosomes are released from all types of cells but in abundance from cancer cells. The contents of exosomes consist of proteins and genetic material (mRNA, DNA and miRNA) from the cell of origin. In this study, we examined the effects of exosomes derived from human lung cancer serum and both highly metastatic and non-metastatic cells on recipient human bronchial epithelial cells (HBECs). We found that exosomes derived from highly metastatic lung cancer cells and human late stage lung cancer serum induced vimentin expression, and epithelial to mesenchymal transition (EMT) in HBECs. Exosomes derived from highly metastatic cancer cells as well as late stage lung cancer serum induce migration, invasion and proliferation in non-cancerous recipient cells. Our results suggest that cancer derived exosomes could be a potential mediator of EMT in the recipient cells.
Subject(s)
Epithelial Cells/metabolism , Epithelial-Mesenchymal Transition/genetics , Exosomes/genetics , Lung Neoplasms/genetics , Adult , Aged , Cell Line , Cell Line, Tumor , Epithelial Cells/pathology , Female , Gene Expression Regulation, Neoplastic , Humans , Male , Middle Aged , RNA Interference , Vimentin/genetics , Vimentin/metabolismABSTRACT
Cancer is the leading cause of death worldwide. Despite significant progress in the field leading to identification of molecular signatures of individual tumors and the development of targeted therapies, early cancer diagnosis remains a clinical challenge. The emerging era of personalized medicine has intensified research towards biomarkers that can be obtained via noninvasive means. The recent discovery of extracellular vesicles (EVs), nano-vesicles secreted by the cell, in circulation has stimulated interest in their clinical utility as cancer biomarkers. EVs are secreted from all types of cells and their contents reflect the physiological and pathological state of the cell. Multiple clinical trials are underway investigating the clinical potential of EV content to serve as biomarkers and therapeutics. However, much work remains to translate EV content into clinical application.
Subject(s)
Biomarkers, Tumor/genetics , Extracellular Vesicles/pathology , MicroRNAs/genetics , Neoplasms/diagnosis , Animals , Extracellular Vesicles/genetics , Humans , Neoplasms/geneticsABSTRACT
Lung cancer is the number one cause of cancer related deaths. The lack of specific and accurate tools for early diagnosis and minimal targeted therapeutics both contribute to poor outcomes. The recent discovery of microRNAs (miRNAs) revealed a novel mechanism for post-transcriptional regulation in cancer and has created new opportunities for the development of diagnostics, prognostics and targeted therapeutics. In lung cancer, miRNA expression profiles distinguish histological subtypes, predict chemotherapeutic response and are associated with prognosis, metastasis and survival. Furthermore, miRNAs circulate in body fluids and hence may serve as important biomarkers for early diagnosis or stratify patients for personalized therapeutic strategies. Here, we provide an overview of the miRNAs implicated in lung cancer, with an emphasis on their clinical utility.
Subject(s)
Biomarkers, Tumor/genetics , Gene Expression Regulation, Neoplastic , Genetic Therapy/methods , Lung Neoplasms , MicroRNAs/genetics , Biomarkers, Tumor/biosynthesis , Humans , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Lung Neoplasms/therapy , MicroRNAs/biosynthesis , PrognosisABSTRACT
Tumor cells have high-energetic and anabolic needs and are known to adapt their metabolism to be able to survive and keep proliferating under conditions of nutrient stress. We show that PKCζ deficiency promotes the plasticity necessary for cancer cells to reprogram their metabolism to utilize glutamine through the serine biosynthetic pathway in the absence of glucose. PKCζ represses the expression of two key enzymes of the pathway, PHGDH and PSAT1, and phosphorylates PHGDH at key residues to inhibit its enzymatic activity. Interestingly, the loss of PKCζ in mice results in enhanced intestinal tumorigenesis and increased levels of these two metabolic enzymes, whereas patients with low levels of PKCζ have a poor prognosis. Furthermore, PKCζ and caspase-3 activities are correlated with PHGDH levels in human intestinal tumors. Taken together, this demonstrates that PKCζ is a critical metabolic tumor suppressor in mouse and human cancer.
Subject(s)
Adenocarcinoma/metabolism , Adenoma/metabolism , Colonic Neoplasms/metabolism , Protein Kinase C/metabolism , Adenomatous Polyposis Coli Protein/genetics , Adenomatous Polyposis Coli Protein/metabolism , Animals , Biosynthetic Pathways , Cell Transformation, Neoplastic , Glucose/metabolism , Humans , Mice , Serine/biosynthesis , Specific Pathogen-Free Organisms , Stress, PhysiologicalABSTRACT
Pten inactivation promotes cell survival in leukemia cells by activating glycolytic metabolism. We found that targeting ribosomal protein S6 kinase 1 (S6K1) in Pten-deficient cells suppressed glycolysis and induced apoptosis. S6K1 knockdown decreased expression of HIF-1α, and HIF-1α was sufficient to restore glycolysis and survival of cells lacking S6K1. In the Pten(fl/fl) Mx1-Cre(+) mouse model of leukemia, S6K1 deletion delayed the development of leukemia. Thus, S6K1 is a critical mediator of glycolytic metabolism, cell survival, and leukemogenesis in Pten-deficient cells.
Subject(s)
Apoptosis , Glycolysis , Leukemia/enzymology , Neoplasm Proteins/metabolism , PTEN Phosphohydrolase/metabolism , Ribosomal Protein S6 Kinases, 90-kDa/metabolism , Animals , Cell Line, Tumor , Disease Models, Animal , Gene Knockdown Techniques , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Leukemia/genetics , Mice , Mice, Knockout , Neoplasm Proteins/genetics , PTEN Phosphohydrolase/genetics , Ribosomal Protein S6 Kinases, 90-kDa/geneticsABSTRACT
We performed a high-throughput screen to identify compounds with a selective ability to induce apoptosis in Akt-expressing cells without disrupting Bcl-xL-dependent survival. Results showed that a screening strategy based on Alamar Blue underrepresented the viability of Bcl-xL-expressing cells relative to Akt-expressing cells, possibly due to metabolic differences between the two cell survival programs. Using an alternative screen based on plasma membrane integrity, we identified several compounds that target Akt-dependent survival without toxic effect to Bcl-xL-dependent survival. These compounds enhanced the cytotoxic potential of rapamycin, a chemotherapeutic that inhibits survival signaling downstream of Akt. The results demonstrate a screening method and the subsequent identification of two compounds with selective activity in counteracting Akt-dependent cell survival.
Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , High-Throughput Screening Assays , Proto-Oncogene Proteins c-akt/metabolism , Sirolimus/pharmacology , bcl-X Protein/metabolism , Animals , Caspase 3/metabolism , Cell Line , Cell Membrane/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Discovery , Drug Screening Assays, Antitumor/methods , Mice , Oxazines , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Signal Transduction/drug effects , Xanthenes , bcl-X Protein/geneticsABSTRACT
Cancer biologists' search for new chemotherapy targets is reinvigorating the study of how cancer cell metabolism determines both oncogenic potential and chemotherapeutic responses. Oncogenic metabolic programs support the bioenergetics associated with resistance to programed cell death and provide biosynthetic building blocks for cell growth and mitogenesis. Both signal transduction pathway activation and direct mutations in key metabolic enzymes can activate the metabolic programs that support cancer cell growth. Cancer-associated metabolic programs include glycolysis, glutamine oxidation, and fatty acid metabolism. Recent observations are revealing the regulatory mechanisms that activate cancer-associated metabolism, and the competitive advantages provided to transformed cells by their metabolic programs. In this study, we review recent results illustrating the mechanisms and functional impact of each of these oncogenic metabolic programs in cancer cell growth and survival.
