13 research outputs found
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Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis
Cancer cells engage in a metabolic program to enhance biosynthesis and support cell proliferation. The regulatory properties of pyruvate kinase M2 (PKM2) influence altered glucose metabolism in cancer. PKM2 interaction with phosphotyrosine-containing proteins inhibits enzyme activity and increases availability of glycolytic metabolites to support cell proliferation. This suggests that high pyruvate kinase activity may suppress tumor growth. We show that expression of PKM1, the pyruvate kinase isoform with high constitutive activity, or exposure to published small molecule PKM2 activators inhibit growth of xenograft tumors. Structural studies reveal that small molecule activators bind PKM2 at the subunit interaction interface, a site distinct from that of the endogenous activator fructose-1,6-bisphosphate (FBP). However, unlike FBP, binding of activators to PKM2 promotes a constitutively active enzyme state that is resistant to inhibition by tyrosine-phosphorylated proteins. These data support the notion that small molecule activation of PKM2 can interfere with anabolic metabolism
Aortic stiffness in young patients with heterozygous familial hypercholesterolemia
Background Dyslipidemia is a primary risk factor for the development of
atherosclerosis. Aortic distensibility is an important determinant of
left ventricular function and coronary blood flow whose possible
alterations in patients with dyslipidemia have not been fully
investigated.
Methods To assess the effect of dyslipidemia on the elastic properties
of the aorta, we studied 60 patients (mean age 37 +/- 11 years) with
heterozygous familial hypercholesterolemia and no manifest arterial
disease and compared them with 20 of their normolipidemic siblings (mean
age 34 +/- 10 years). Two indexes of the aortic elastic properties were
measured: aortic distensibility was calculated by use of the formula: 2
x (AoS-AoD)/PP x AoD, and aortic stiffness index was calculated by use
of the formula: In (SBP/DBP)/(AoS-AoD)/AoD, where AoS and AoD ore aortic
root end-systolic and end-diastolic diameters, respectively, SEP and DBP
are systolic and diastolic arterial pressure, respectively, and PP is
pulse pressure. Internal aortic root diameters were measured at 3 cm
above the aortic valve by use of two-dimensional guided M-mode
transthoracic echocardiography, and arterial pressure was measured
simultaneously at the brachial artery by sphygmomanometry.
Results The mean aortic systolic and diastolic diameter index did not
differ signifficantly between the two groups. In contrast, aortic
distensibility was found to be significantly reduced in subjects with
isolated familial hypercholesterolemia compared with that in the control
group (2.15 +/- 1.72 cm(2).dynes.10(-6)vs 3.18 +/- 1.58
cm(2).dynes(-1).10(-6), p < 0.02), In addition, the mean aortic
stiffness index was double in patients with familial
hypercholesterolemia compared with that in normolipidemic subjects.
Conclusions severe dyslipidemia does not overtly influence aortic
dimensions but leads to impairment of aortic elastic properties before
the occurrence of clinical manifestations of atherosclerotic disease
Recommended from our members
Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis.
Cancer cells engage in a metabolic program to enhance biosynthesis and support cell proliferation. The regulatory properties of pyruvate kinase M2 (PKM2) influence altered glucose metabolism in cancer. The interaction of PKM2 with phosphotyrosine-containing proteins inhibits enzyme activity and increases the availability of glycolytic metabolites to support cell proliferation. This suggests that high pyruvate kinase activity may suppress tumor growth. We show that expression of PKM1, the pyruvate kinase isoform with high constitutive activity, or exposure to published small-molecule PKM2 activators inhibits the growth of xenograft tumors. Structural studies reveal that small-molecule activators bind PKM2 at the subunit interaction interface, a site that is distinct from that of the endogenous activator fructose-1,6-bisphosphate (FBP). However, unlike FBP, binding of activators to PKM2 promotes a constitutively active enzyme state that is resistant to inhibition by tyrosine-phosphorylated proteins. These data support the notion that small-molecule activation of PKM2 can interfere with anabolic metabolism