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Greater transiency in modulation of gene expression is the predominant difference between the actions of bryostatin 1 and phorbol ester in LNCaP and U937 cells

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE104377 | GEO | 2017/12/30

SECONDARY ACCESSION(S): PRJNA412471

REPOSITORIES: GEO

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Greater transiency in modulation of gene expression is the predominant difference between the actions of bryostatin 1 and phorbol ester in LNCaP and U937 cells [set 2]

Project description:Bryostatin 1, like the phorbol ester PMA, activates protein kinase C (PKC) in vitro but paradoxically blocks many phorbol ester responses in vivo. Results with a limited panel of genes suggested that transiency of action was an important mechanism contributing to this differential cellular response. Here, we examined global gene expression in LNCaP and U937 cell lines to probe the extent to which transiency of action captures the difference in response. While different genes showed different patterns of relative response, the overall pattern was reflective of an initial PMA-like response to bryostatin 1 followed by variable transiency of the continued response. This conclusion was further strengthened by detailed time course measurements by qPCR of selected genes. Merle 23, a bryostatin derivative with biological behavior intermediate between that of bryostatin 1 and PMA, was likewise intermediate for transiency of action. Both the LNCaP and U937 cell lines behaved similarly, but the extent of transiency in response to bryostatin 1 was greater in the LNCaP cells.

2017-12-30 | GSE104374 | GEO

Greater transiency in modulation of gene expression is the predominant difference between the actions of bryostatin 1 and phorbol ester in LNCaP and U937 cells [set 1]

2017-12-30 | GSE104373 | GEO

Some phorbol esters might partially resemble bryostatin 1 in their actions on LNCaP prostate cancer cells and U937 leukemia cells.

Project description:Phorbol 12-myristate 13-acetate (PMA) and bryostatin 1 are both potent protein kinase C (PKC) activators. In LNCaP human prostate cancer cells, PMA induces tumor necrosis factor alpha (TNF?) secretion and inhibits proliferation; bryostatin 1 does not, and indeed blocks the response to PMA. This difference has been attributed to bryostatin 1 not localizing PKC? to the plasma membrane. Since phorbol ester lipophilicity influences PKC? localization, we have examined in LNCaP cells a series of phorbol esters and related derivatives spanning some eight logs in lipophilicity (logP) to see if any behave like bryostatin 1. The compounds showed marked differences in their effects on proliferation and TNF? secretion. For example, maximal responses for TNF? secretion relative to PMA ranged from 97?% for octyl-indolactam V to 24?% for phorbol 12,13-dibenzoate. Dose-response curves ranged from monophasic for indolactam V to markedly biphasic for sapintoxin D. The divergent patterns of response, however, correlated neither to lipophilicity, to plasma membrane translocation of PKC?, nor to the ability to interact with model membranes. In U937 human leukemia cells, a second system in which PMA and bryostatin 1 have divergent effects, viz. PMA but not bryostatin 1 inhibits proliferation and induces attachment, all the compounds acted like PMA for proliferation, but several induced a reduced level or a biphasic dose-response curve for attachment. We conclude that active phorbol esters are not all equivalent. Depending on the system, some might partially resemble bryostatin 1 in their behavior; this encourages the concept that bryostatin-like behavior may be obtained from other structural templates.

| S-EPMC3313843 | biostudies-literature

Comparison of transcriptional response to phorbol ester, bryostatin 1, and bryostatin analogs in LNCaP and U937 cancer cell lines provides insight into their differential mechanism of action.

Project description:Bryostatin 1, like the phorbol esters, binds to and activates protein kinase C (PKC) but paradoxically antagonizes many but not all phorbol ester responses. Previously, we have compared patterns of biological response to bryostatin 1, phorbol ester, and the bryostatin 1 derivative Merle 23 in two human cancer cell lines, LNCaP and U937. Bryostatin 1 fails to induce a typical phorbol ester biological response in either cell line, whereas Merle 23 resembles phorbol ester in the U937 cells and bryostatin 1 in the LNCaP cells. Here, we have compared the pattern of their transcriptional response in both cell lines. We examined by qPCR the transcriptional response as a function of dose and time for a series of genes regulated by PKCs. In both cell lines bryostatin 1 differed primarily from phorbol ester in having a shorter duration of transcriptional modulation. This was not due to bryostatin 1 instability, since bryostatin 1 suppressed the phorbol ester response. In both cell lines Merle 23 induced a pattern of transcription largely like that of phorbol ester although with a modest reduction at later times in the LNCaP cells, suggesting that the difference in biological response of the two cell lines to Merle 23 lies downstream of this transcriptional regulation. For a series of bryostatins and analogs which ranged from bryostatin 1-like to phorbol ester-like in activity on the U937 cells, the duration of transcriptional response correlated with the pattern of biological activity, suggesting that this may provide a robust platform for structure activity analysis.

| S-EPMC3553297 | biostudies-literature

Greater transiency in modulation of gene expression is the predominant difference between the actions of bryostatin 1 and phorbol ester in LNCaP and U937 cells

Project description:Greater transiency in modulation of gene expression is the predominant difference between the actions of bryostatin 1 and phorbol ester in LNCaP and U937 cells

| PRJNA412471 | ENA

Greater transiency in modulation of gene expression is the predominant difference between the actions of bryostatin 1 and phorbol ester in LNCaP and U937 cells [set 2]

Project description:Greater transiency in modulation of gene expression is the predominant difference between the actions of bryostatin 1 and phorbol ester in LNCaP and U937 cells [set 2]

| PRJNA412465 | ENA

Greater transiency in modulation of gene expression is the predominant difference between the actions of bryostatin 1 and phorbol ester in LNCaP and U937 cells [set 1]

Project description:Greater transiency in modulation of gene expression is the predominant difference between the actions of bryostatin 1 and phorbol ester in LNCaP and U937 cells [set 1]

| PRJNA412466 | ENA

Convergent assembly of highly potent analogues of bryostatin 1 via pyran annulation: bryostatin look-alikes that mimic phorbol ester function.

Project description:Highly potent bryostatin analogues which contain the complete bryostatin core structure have been synthesized using a pyran annulation approach as a key strategic element. The A ring pyran was assembled using a pyran annulation reaction between a C1-C8 hydroxy allylsilane and an aldehyde comprising C9-C13. This pyran was transformed to a new hydroxy allylsilane and then coupled with a preformed C ring aldehyde subunit in a second pyran annulation, with concomitant formation of the B ring. This tricyclic intermediate was elaborated to bryostatin analogues which displayed nanomolar to subnanomolar affinity for PKC, but displayed properties indistinguishable from a phorbol ester in a proliferation/attachment assay.

| S-EPMC2516406 | biostudies-literature

The bryostatin 1 A-ring acetate is not the critical determinant for antagonism of phorbol ester-induced biological responses.

Project description:The contribution of the A-ring C(7) acetate to the function of bryostatin 1 has been investigated through synthesis and biological evaluation of an analogue incorporating this feature into the bryopyran core structure. No enhanced binding affinity for protein kinase C (PKC) was observed, relative to previously characterized analogues lacking the C(7) acetate. Functional assays showed biological responses characteristic of those induced by the phorbol ester PMA and distinctly different from those observed with bryostatin 1.

| S-EPMC3075950 | biostudies-literature

The synthetic bryostatin analog Merle 23 dissects distinct mechanisms of bryostatin activity in the LNCaP human prostate cancer cell line.

Project description:Bryostatin 1 has attracted considerable attention both as a cancer chemotherapeutic agent and for its unique activity. Although it functions, like phorbol esters, as a potent protein kinase C (PKC) activator, it paradoxically antagonizes many phorbol ester responses in cells. Because of its complex structure, little is known of its structure-function relations. Merle 23 is a synthetic derivative, differing from bryostatin 1 at only four positions. However, in U-937 human leukemia cells, Merle 23 behaves like a phorbol ester and not like bryostatin 1. Here, we characterize the behavior of Merle 23 in the human prostate cancer cell line LNCaP. In this system, bryostatin 1 and phorbol ester have contrasting activities, with the phorbol ester but not bryostatin 1 blocking cell proliferation or tumor necrosis factor alpha secretion, among other responses. We show that Merle 23 displays a highly complex pattern of activity in this system. Depending on the specific biological response or mechanistic change, it was bryostatin-like, phorbol ester-like, intermediate in its behavior, or more effective than either. The pattern of response, moreover, varied depending on the conditions. We conclude that the newly emerging bryostatin derivatives such as Merle 23 provide powerful tools to dissect subsets of bryostatin mechanism and response.

| S-EPMC3089703 | biostudies-literature

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