Integrin Priming Dynamics: Mechanisms of Integrin Antagonist-Promoted αIIbβ3:PAC-1 Molecular Recognition

Hantgan, Roy R.; Stahle, Mary C.

doi:10.1021/bi900475k

Cited by 44 publications

(63 citation statements)

References 52 publications

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“…Activation of CASP3 may also sensitize cancer cells to other agents, such as chemotherapy. In this study, we sought to analyze whether a caspase 3 activator, PAC-1, 25 which activates procaspase-3 by chelating zinc and thus relieves the zinc-mediated inhibition of this zymogen, had anti-proliferative effects in lung adenocarcinoma cells, and whether there were synergistic effects in combination with Cis, a key chemotherapeutic agent, in these cancer cells. Our IHC data regarding CASP3 expression showed that CASP3 was overexpressed in some lung cancers (Fig.…”

Section: Discussionmentioning

confidence: 99%

Synergistic antitumor activity of pro‐apoptotic agent PAC‐1 with cisplatinum by the activation of CASP3 in pulmonary adenocarcinoma cell line H1299

Huang

Liang

Zhang

et al. 2015

Asia-Pac J Clncl Oncology

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Aim: Evasion of apoptosis is a hallmark of human cancer cells. We sought to explore the potential synergistic antitumor activity and underlying mechanisms of the pro-apoptotic agent PAC-1 plus cisplatinum (Cis) in non-small cell lung cancer (NSCLC) cell lines. Methods: The adenocarcinoma cell lines H1299, A549, PC9, H1650 and H1975 were used as in vitro models. Colorimetric MTT assays, Western blotting and flow cytometry were used to evaluate the antigrowth effects of PAC-1 and/or Cis and apoptosis status. The activated form of CASP3 (C-CASP3) was assessed by immunofluorescent staining. Results: Single-agent Cis and PAC-1 were able to inhibit the cancer cell growth in certain dose ranges, with IC 50 values of 1.9-11.7 and 5.6-14.8 μM, respectively. Sequential Cis→PAC-1 or concurrent Cis + PAC-1, but not PAC-1→Cis combinations showed synergistic effects on cell growth inhibition in H1299 cells (combination index, CI ≤ 0.6). In contrast, other combination modes mostly showed seemingly antagonistic effects (CI > 1.0). Flow cytometric analysis showed that Cis→PAC-1 sequential combination showed strong proapoptotic effects in H1299 cells. Western blots showed that in H1299, PC9 and H1975 cells, PAC-1 promoted the C-CASP3, but only in H1299 cells was there a synergistic effect with Cis on the CASP3 activation. Conclusions: PAC-1 showed anti-tumor activity in NSCLCs in vitro and a synergistic effect with cisplatin in EGFR wt KRAS wt H1299 cells. Our data suggest a potential treatment approach using cisplatin plus a pro-apoptotic agent acting via CASP3 activation for this subgroup of pulmonary adenocarcinomas.

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Section: Discussionmentioning

confidence: 99%

Synergistic antitumor activity of pro‐apoptotic agent PAC‐1 with cisplatinum by the activation of CASP3 in pulmonary adenocarcinoma cell line H1299

Huang

Liang

Zhang

et al. 2015

Asia-Pac J Clncl Oncology

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“…A Biacore T100 SPR platform ( 22,23 ) was used to quantify the interaction of LDL with immobilized BGN. In the fi rst step, the dextran surfaces of a CM5 biosensor chip (Biacore, Inc.; Piscataway, NJ), for both reference and sample channels, were activated for amine coupling ( 22 ).…”

Section: Ldl-bgn Interactionmentioning

confidence: 99%

“…In the fi rst step, the dextran surfaces of a CM5 biosensor chip (Biacore, Inc.; Piscataway, NJ), for both reference and sample channels, were activated for amine coupling ( 22 ). Following surface activation, an antigen affi nity-purifi ed polyclonal goat IgG, specifi c to BGN core protein (R and D Systems; AF2667), was covalently coupled to the dextran surface of the chip through its lysine residues, reproducibly yielding a sparse IgG monolayer in both channels signifi cant positive association between the percentage of plasma CE as CO and carotid artery intima-media thickness in patients with preclinical atherosclerosis ( 13 ).…”

Section: Ldl-bgn Interactionmentioning

confidence: 99%

LDL particle core enrichment in cholesteryl oleate increases proteoglycan binding and promotes atherosclerosis

Melchior

Sawyer

Kelley

et al. 2013

Journal of Lipid Research

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the pathophysiology of atherosclerosis ( 2 ). After LDL particles enter the intima of the artery wall, they can interact with proteoglycans, which are structural proteins residing in the extracellular matrix that consist of one or more glycosaminoglycan (GAG) side-chains attached to core proteins. The LDL-proteoglycan complex is generally regarded as an electrostatic interaction ( 3 ). The sulfation pattern of the acidic sugar groups that form the GAG chains on the proteoglycans results in an overall negative charge that can interact with clusters of positively charged amino acid residues on apoB-100, the primary apolipoprotein present on the LDL particle ( 4 ). A proteoglycan frequently deposited in atherosclerotic plaques of humans ( 5, 6 ) and mice is biglycan (BGN) ( 7 ).While plasma LDL cholesterol concentrations are predictive of the extent of atherosclerosis, LDL particles are heterogeneous in size and composition, and this heterogeneity may provide additional useful information about the role of LDL in atherosclerosis. For instance, studies have shown that diet-induced alterations in the FA composition of LDL core cholesteryl esters (CEs) can infl uence the atherogenic potential of LDL particles ( 8-11 ). In nonhuman primates, consumption of dietary MUFAs resulted in LDL particles containing a CE core enriched in cholesterol oleate (CO), which were positively associated with coronary artery atherosclerosis ( r = 0.8) ( 10, 11 ). Importantly, a similar diet-related shift in the CE FA composition of LDL has been observed in humans in which consumption of oleate-enriched diets resulted in elevations in the percentage of CO in the LDL CE ( 12 ). Additionally, the large Atherosclerosis Risk in Communities Study revealed a Abstract Several studies in humans and animals suggest that LDL particle core enrichment in cholesteryl oleate (CO) is associated with increased atherosclerosis. Diet enrichment with MUFAs enhances LDL CO content. Steroyl O -acyltransferase 2 (SOAT2) is the enzyme that catalyzes the synthesis of much of the CO found in LDL, and gene deletion of SOAT2 minimizes CO in LDL and protects against atherosclerosis. The purpose of this study was to test the hypothesis that the increased atherosclerosis associated with LDL core enrichment in CO results from an increased affi nity of the LDL particle for arterial proteoglycans. ApoB-100-only Ldlr − /− mice with and without Soat2 gene deletions were fed diets enriched in either cis -MUFA or n-3 PUFA, and LDL particles were isolated. LDL:proteogylcan binding was measured using surface plasmon resonance. Particles with higher CO content consistently bound with higher affi nity to human biglycan and the amount of binding was shown to be proportional to the extent of atherosclerosis of the LDL donor mice. The data strongly support the thesis that atherosclerosis was induced through enhanced proteoglycan binding of LDL resulting from LDL core CO

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“…studies show fibrinogen binding is a time-dependent multistep process leading to higher-affinity and lack of reversibility. 9,10,[12][13][14][15][16][17][18][19][20][21][22] (2) When reversibly dissociated, both aIIb and b3 can bind to immobilized fibrinogen. 16 (3) Platelets can adhere to fibrinogen fragments lacking g-404-411, 23,24 but it is unclear whether the platelets need to be activated in order to bind.…”

Section: Introductionmentioning

confidence: 99%

αIIbβ3 binding to a fibrinogen fragment lacking the γ-chain dodecapeptide is activation dependent and EDTA inducible

Zafar

Shang

et al. 2017

Blood Advances

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Key Points• Activation of aIIbb3 is required for its ancillary site interactions with fibrinogen fragment D lacking the g-chain dodecapeptide ('D98').• EDTA can paradoxically induce normal aIIbb3 to interact with fibrinogen fragment 'D98.'Platelet integrin receptor aIIbb3 supports platelet aggregation by binding fibrinogen. The interaction between the fibrinogen C-terminal g-chain peptide composed of residues g-404-411 (GAKQAGDV) and the Arg-Gly-Asp (RGD) binding pocket on aIIbb3 is required for fibrinogen-mediated platelet aggregation, but data suggest that other ancillary binding sites on both fibrinogen and aIIbb3 may lead to higher-affinity fibrinogen binding and clot retraction. To identify additional sites, we analyzed the ability of platelets and cells expressing normal and mutant aIIbb3 to adhere to an immobilized fibrinogen plasmin fragment that lacks intact g-404-411 ('D98'). We found the following: (1) Activated, but not unactivated, platelets adhere well to immobilized 'D98.' (2) Cells expressing constitutively active aIIbb3 mutants, but not cells expressing normal aIIbb3 or aVb3, adhere well to 'D98.' Because molecular modeling and molecular dynamics simulations suggested that the aIIb L151-D159 helix may contribute to the interaction with 'D98,' we studied an aIIbb3 mutant in which the aIIb 148-166 loop was swapped with the corresponding aV loop; it failed to bind to fibrinogen or 'D98.' Our data support a model in which conformational changes in aIIbb3and/or fibrinogen after platelet activation and the interaction between g-404-411 and the RGD binding pocket make new ancillary sites available that support higher-affinity fibrinogen binding and clot retraction.

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Integrin Priming Dynamics: Mechanisms of Integrin Antagonist-Promoted αIIbβ3:PAC-1 Molecular Recognition

Cited by 44 publications

References 52 publications

Synergistic antitumor activity of pro‐apoptotic agent PAC‐1 with cisplatinum by the activation of CASP3 in pulmonary adenocarcinoma cell line H1299

Synergistic antitumor activity of pro‐apoptotic agent PAC‐1 with cisplatinum by the activation of CASP3 in pulmonary adenocarcinoma cell line H1299

LDL particle core enrichment in cholesteryl oleate increases proteoglycan binding and promotes atherosclerosis

αIIbβ3 binding to a fibrinogen fragment lacking the γ-chain dodecapeptide is activation dependent and EDTA inducible

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