Supplementary Figure S5 shows the effect of MBQ compounds on Rac activation in attached and detac... more Supplementary Figure S5 shows the effect of MBQ compounds on Rac activation in attached and detached cells.
Rac and Cdc42, are homologous GTPases that regulate cell migration, invasion, and cell-cycle prog... more Rac and Cdc42, are homologous GTPases that regulate cell migration, invasion, and cell-cycle progression; thus, representing key targets for metastasis therapy. We previously reported on the efficacy of MBQ-167, which blocks both Rac1 and Cdc42 in breast cancer cells and mouse models of metastasis. To identify compounds with increased activity, a panel of MBQ-167 derivatives was synthesized, maintaining its 9-ethyl-3-(1H-1,2,3-triazol-1-yl)-9H-carbazole core. Similar to MBQ-167, MBQ-168 and EHop-097 inhibit activation of Rac and Rac1B splice variant and breast cancer cell viability, and induce apoptosis. MBQ-167 and MBQ-168 inhibit Rac and Cdc42 by interfering with guanine nucleotide binding, and MBQ-168 is a more effective inhibitor of P21-activated kinase (1–3) activation. EHop-097 acts via a different mechanism by inhibiting the interaction of the guanine nucleotide exchange factor Vav with Rac. MBQ-168 and EHop-097 inhibit metastatic breast cancer cell migration, and MBQ-168 promotes loss of cancer cell polarity to result in disorganization of the actin cytoskeleton and detachment from the substratum. In lung cancer cells, MBQ-168 is more effective than MBQ-167 or EHop-097 at reducing ruffle formation in response to EGF. Comparable with MBQ-167, MBQ-168 significantly inhibits HER2-positive tumor growth and metastasis to lung, liver, and spleen. Both MBQ-167 and MBQ-168 inhibit the cytochrome P450 (CYP) enzymes 3A4, 2C9, and 2C19. However, MBQ-168 is approximately 10× less potent than MBQ-167 at inhibiting CYP3A4, thus demonstrating its utility in relevant combination therapies. In conclusion, the MBQ-167 derivatives MBQ-168 and EHop-097 are additional promising antimetastatic cancer compounds with similar and distinct mechanisms.Significance:Targeting the related GTPases Rac and Cdc42 that regulate cancer metastasis is a viable strategy to impede metastasis of solid cancers. Herein, we describe new Rac and Cdc42 inhibitors with unique mechanisms and varying potency in different cancer cell lines. The MBQ-167 derivatives MBQ-168 and EHop-097 show promise as potential antimetastatic cancer agents.
Aberrant expression of protein kinase C (PKC) isozymes is a hallmark of cancer. The different mem... more Aberrant expression of protein kinase C (PKC) isozymes is a hallmark of cancer. The different members of the PKC family control cellular events associated with cancer development and progression. Whereas the classical/conventional PKCα isozyme has been linked to tumor suppression in most cancer types, here we demonstrate that this kinase is required for the mitogenic activity of aggressive human prostate cancer cells displaying aberrantly high PKCα expression. IHC analysis showed abnormal upregulation of PKCα in human primary prostate tumors. Interestingly, silencing PKCα expression from aggressive prostate cancer cells impairs cell-cycle progression, proliferation, and invasion, as well as their tumorigenic activity in a mouse xenograft model. Mechanistic analysis revealed that PKCα exerts a profound control of gene expression, particularly over genes and transcriptional networks associated with cell-cycle progression and E2F transcription factors. PKCα RNAi depletion from PC3 prostate cancer cells led to a reduction in the expression of proinflammatory cytokine and epithelial-to-mesenchymal transition (EMT) genes, as well as a prominent downregulation of the immune checkpoint ligand PD-L1. This PKCα-dependent gene expression profile was corroborated in silico using human prostate cancer databases. Our studies established PKCα as a multifunctional kinase that plays pleiotropic roles in prostate cancer, particularly by controlling genetic networks associated with tumor growth and progression. The identification of PKCα as a protumorigenic kinase in human prostate cancer provides strong rationale for the development of therapeutic approaches toward targeting PKCα or its effectors.Significance:PKCα was found to be aberrantly expressed in human prostate cancer. Silencing the expression of this kinase from aggressive prostate cancer cell lines reduces their proliferative, tumorigenic, and invasive properties. In addition, our findings implicate PKCα as a major node for transcriptional regulation of tumorigenic, inflammatory, and EMT networks in prostate cancer, highlighting its potential relevance as a therapeutic target.
Supplementary Figure S7 shows the effect of MBQ-167 on Rac1(G15A) association with Tiam-1 and p-R... more Supplementary Figure S7 shows the effect of MBQ-167 on Rac1(G15A) association with Tiam-1 and p-REX-1.
Supplementary Figure S5 shows the effect of MBQ compounds on Rac activation in attached and detac... more Supplementary Figure S5 shows the effect of MBQ compounds on Rac activation in attached and detached cells.
Rac and Cdc42, are homologous GTPases that regulate cell migration, invasion, and cell-cycle prog... more Rac and Cdc42, are homologous GTPases that regulate cell migration, invasion, and cell-cycle progression; thus, representing key targets for metastasis therapy. We previously reported on the efficacy of MBQ-167, which blocks both Rac1 and Cdc42 in breast cancer cells and mouse models of metastasis. To identify compounds with increased activity, a panel of MBQ-167 derivatives was synthesized, maintaining its 9-ethyl-3-(1H-1,2,3-triazol-1-yl)-9H-carbazole core. Similar to MBQ-167, MBQ-168 and EHop-097 inhibit activation of Rac and Rac1B splice variant and breast cancer cell viability, and induce apoptosis. MBQ-167 and MBQ-168 inhibit Rac and Cdc42 by interfering with guanine nucleotide binding, and MBQ-168 is a more effective inhibitor of P21-activated kinase (1–3) activation. EHop-097 acts via a different mechanism by inhibiting the interaction of the guanine nucleotide exchange factor Vav with Rac. MBQ-168 and EHop-097 inhibit metastatic breast cancer cell migration, and MBQ-168 pro...
Reduced production of cytokines in PC3 cells subjected to PKCalpha RNAi depletion. IL-8 and GRO w... more Reduced production of cytokines in PC3 cells subjected to PKCalpha RNAi depletion. IL-8 and GRO were measured in conditioned medium of PC3 cells by ELISA.
Supplementary Figure S5 shows the effect of MBQ compounds on Rac activation in attached and detac... more Supplementary Figure S5 shows the effect of MBQ compounds on Rac activation in attached and detached cells.
Rac and Cdc42, are homologous GTPases that regulate cell migration, invasion, and cell-cycle prog... more Rac and Cdc42, are homologous GTPases that regulate cell migration, invasion, and cell-cycle progression; thus, representing key targets for metastasis therapy. We previously reported on the efficacy of MBQ-167, which blocks both Rac1 and Cdc42 in breast cancer cells and mouse models of metastasis. To identify compounds with increased activity, a panel of MBQ-167 derivatives was synthesized, maintaining its 9-ethyl-3-(1H-1,2,3-triazol-1-yl)-9H-carbazole core. Similar to MBQ-167, MBQ-168 and EHop-097 inhibit activation of Rac and Rac1B splice variant and breast cancer cell viability, and induce apoptosis. MBQ-167 and MBQ-168 inhibit Rac and Cdc42 by interfering with guanine nucleotide binding, and MBQ-168 is a more effective inhibitor of P21-activated kinase (1–3) activation. EHop-097 acts via a different mechanism by inhibiting the interaction of the guanine nucleotide exchange factor Vav with Rac. MBQ-168 and EHop-097 inhibit metastatic breast cancer cell migration, and MBQ-168 promotes loss of cancer cell polarity to result in disorganization of the actin cytoskeleton and detachment from the substratum. In lung cancer cells, MBQ-168 is more effective than MBQ-167 or EHop-097 at reducing ruffle formation in response to EGF. Comparable with MBQ-167, MBQ-168 significantly inhibits HER2-positive tumor growth and metastasis to lung, liver, and spleen. Both MBQ-167 and MBQ-168 inhibit the cytochrome P450 (CYP) enzymes 3A4, 2C9, and 2C19. However, MBQ-168 is approximately 10× less potent than MBQ-167 at inhibiting CYP3A4, thus demonstrating its utility in relevant combination therapies. In conclusion, the MBQ-167 derivatives MBQ-168 and EHop-097 are additional promising antimetastatic cancer compounds with similar and distinct mechanisms.Significance:Targeting the related GTPases Rac and Cdc42 that regulate cancer metastasis is a viable strategy to impede metastasis of solid cancers. Herein, we describe new Rac and Cdc42 inhibitors with unique mechanisms and varying potency in different cancer cell lines. The MBQ-167 derivatives MBQ-168 and EHop-097 show promise as potential antimetastatic cancer agents.
Aberrant expression of protein kinase C (PKC) isozymes is a hallmark of cancer. The different mem... more Aberrant expression of protein kinase C (PKC) isozymes is a hallmark of cancer. The different members of the PKC family control cellular events associated with cancer development and progression. Whereas the classical/conventional PKCα isozyme has been linked to tumor suppression in most cancer types, here we demonstrate that this kinase is required for the mitogenic activity of aggressive human prostate cancer cells displaying aberrantly high PKCα expression. IHC analysis showed abnormal upregulation of PKCα in human primary prostate tumors. Interestingly, silencing PKCα expression from aggressive prostate cancer cells impairs cell-cycle progression, proliferation, and invasion, as well as their tumorigenic activity in a mouse xenograft model. Mechanistic analysis revealed that PKCα exerts a profound control of gene expression, particularly over genes and transcriptional networks associated with cell-cycle progression and E2F transcription factors. PKCα RNAi depletion from PC3 prostate cancer cells led to a reduction in the expression of proinflammatory cytokine and epithelial-to-mesenchymal transition (EMT) genes, as well as a prominent downregulation of the immune checkpoint ligand PD-L1. This PKCα-dependent gene expression profile was corroborated in silico using human prostate cancer databases. Our studies established PKCα as a multifunctional kinase that plays pleiotropic roles in prostate cancer, particularly by controlling genetic networks associated with tumor growth and progression. The identification of PKCα as a protumorigenic kinase in human prostate cancer provides strong rationale for the development of therapeutic approaches toward targeting PKCα or its effectors.Significance:PKCα was found to be aberrantly expressed in human prostate cancer. Silencing the expression of this kinase from aggressive prostate cancer cell lines reduces their proliferative, tumorigenic, and invasive properties. In addition, our findings implicate PKCα as a major node for transcriptional regulation of tumorigenic, inflammatory, and EMT networks in prostate cancer, highlighting its potential relevance as a therapeutic target.
Supplementary Figure S7 shows the effect of MBQ-167 on Rac1(G15A) association with Tiam-1 and p-R... more Supplementary Figure S7 shows the effect of MBQ-167 on Rac1(G15A) association with Tiam-1 and p-REX-1.
Supplementary Figure S5 shows the effect of MBQ compounds on Rac activation in attached and detac... more Supplementary Figure S5 shows the effect of MBQ compounds on Rac activation in attached and detached cells.
Rac and Cdc42, are homologous GTPases that regulate cell migration, invasion, and cell-cycle prog... more Rac and Cdc42, are homologous GTPases that regulate cell migration, invasion, and cell-cycle progression; thus, representing key targets for metastasis therapy. We previously reported on the efficacy of MBQ-167, which blocks both Rac1 and Cdc42 in breast cancer cells and mouse models of metastasis. To identify compounds with increased activity, a panel of MBQ-167 derivatives was synthesized, maintaining its 9-ethyl-3-(1H-1,2,3-triazol-1-yl)-9H-carbazole core. Similar to MBQ-167, MBQ-168 and EHop-097 inhibit activation of Rac and Rac1B splice variant and breast cancer cell viability, and induce apoptosis. MBQ-167 and MBQ-168 inhibit Rac and Cdc42 by interfering with guanine nucleotide binding, and MBQ-168 is a more effective inhibitor of P21-activated kinase (1–3) activation. EHop-097 acts via a different mechanism by inhibiting the interaction of the guanine nucleotide exchange factor Vav with Rac. MBQ-168 and EHop-097 inhibit metastatic breast cancer cell migration, and MBQ-168 pro...
Reduced production of cytokines in PC3 cells subjected to PKCalpha RNAi depletion. IL-8 and GRO w... more Reduced production of cytokines in PC3 cells subjected to PKCalpha RNAi depletion. IL-8 and GRO were measured in conditioned medium of PC3 cells by ELISA.
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