Integrins and Cell Metabolism: An Intimate Relationship Impacting Cancer.

Integrins are important regulators of cell survival, proliferation, adhesion and migration. Once activated, integrins establish a regulated link between the extracellular matrix and the cytoskeleton. Integrins have well-established functions in cancer, such as in controlling cell survival by engagement of many specific intracellular signaling pathways and in facilitating metastasis. Integrins and associated proteins are regulated by control of transcription, membrane traffic, and degradation, as well as by a number of post-translational modifications including glycosylation, allowing integrin function to be modulated to conform to various cellular needs and environmental conditions. In this review, we examine the control of integrin function by cell metabolism, and the impact of this regulation in cancer. Within this context, nutrient sufficiency or deprivation is sensed by a number of metabolic signaling pathways such as AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR) and hypoxia-inducible factor (HIF) 1, which collectively control integrin function by a number of mechanisms. Moreover, metabolic flux through specific pathways also controls integrins, such as by control of integrin glycosylation, thus impacting integrin-dependent cell adhesion and migration. Integrins also control various metabolic signals and pathways, establishing the reciprocity of this regulation. As cancer cells exhibit substantial changes in metabolism, such as a shift to aerobic glycolysis, enhanced glucose utilization and a heightened dependence on specific amino acids, the reciprocal regulation of integrins and metabolism may provide important clues for more effective treatment of various cancers.

AMP-Activated Protein Kinase Regulates the Cell Surface Proteome and Integrin Membrane Traffic.

The cell surface proteome controls numerous cellular functions including cell migration and adhesion, intercellular communication and nutrient uptake. Cell surface proteins are controlled by acute changes in protein abundance at the plasma membrane through regulation of endocytosis and recycling (endomembrane traffic). Many cellular signals regulate endomembrane traffic, including metabolic signaling; however, the extent to which the cell surface proteome is controlled by acute regulation of endomembrane traffic under various conditions remains incompletely understood. AMP-activated protein kinase (AMPK) is a key metabolic sensor that is activated upon reduced cellular energy availability. AMPK activation alters the endomembrane traffic of a few specific proteins, as part of an adaptive response to increase energy intake and reduce energy expenditure. How increased AMPK activity during energy stress may globally regulate the cell surface proteome is not well understood. To study how AMPK may regulate the cell surface proteome, we used cell-impermeable biotinylation to selectively purify cell surface proteins under various conditions. Using ESI-MS/MS, we found that acute (90 min) treatment with the AMPK activator A-769662 elicits broad control of the cell surface abundance of diverse proteins. In particular, A-769662 treatment depleted from the cell surface proteins with functions in cell migration and adhesion. To complement our mass spectrometry results, we used other methods to show that A-769662 treatment results in impaired cell migration. Further, A-769662 treatment reduced the cell surface abundance of ß1-integrin, a key cell migration protein, and AMPK gene silencing prevented this effect. While the control of the cell surface abundance of various proteins by A-769662 treatment was broad, it was also selective, as this treatment did not change the cell surface abundance of the transferrin receptor. Hence, the cell surface proteome is subject to acute regulation by treatment with A-769662, at least some of which is mediated by the metabolic sensor AMPK.

Outcome of cardiogenic shock complicating acute myocardial infarction.

OBJECTIVE: To analyze the characteristics and in-hospital outcome of patients with cardiogenic shock (CS) complicating acute myocardial infarction (AMI) and to evaluate the influence of urgent coronary revascularization on in-hospital mortality. DESIGN: Descriptive study. PLACE AND DURATION OF STUDY: The Aga Khan University Hospital, Karachi. January 2001 to December 2001. MATERIALS AND METHODS: All consecutive patients with AMI and CS, admitted at The Aga Khan University Hospital, Karachi Pakistan, during the year 2001 were reviewed. A pre-designed questionnaire was used for data collection. Analysis was done using the SPSS statistical package. RESULTS: Out of 615 patients with AMI, 53 (8.6%) had CS. Mean age was 60.9 +10.7 years. 62.3% were men, 52.8% were hypertensive and 43.4% were diabetic. Most infarcts were anterior in location (56.6%). Thrombolytic therapy (Streptokinase) was administered to 43.5% of patients with ST segment elevation myocardial infarction. 64.2% required ventilatory support while swan ganz was used in 37.7%. Intra-aortic balloon pump was inserted in 39.6%. Ventricular tachycardia was the most common complication (39.6%). Overall in-hospital mortality was 54.7%. CS associated with mechanical complications had 80% in-hospital mortality. In patients without mechanical complications (n=48), in-hospital mortality was significantly lower in the revascularization group (31.6% vs. 65.5%, p-value = 0.021). However, there were significant differences in the baseline characteristics in the two groups because of the selection bias. CONCLUSION: CS occurring in patients with AMI has an extremely poor prognosis. Patients selected for revascularization strategy has favorable in-hospital outcome.