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Breast cancer genes PSMC3IP and EPSTI1 play a role in apoptosis regulation.

Capdevila-Busquets E, Badiola N, Arroyo R, Alcalde V, Soler-López M, Aloy P - PLoS ONE (2015)

Bottom Line: A key element to delineate the biology of individual tumors is the regulation of apoptosis.We first explore the existence of direct physical interactions with annotated BC-apoptotic genes.Based on the generated interaction network, we examine several apoptotic markers to determine the effect of PSMC3IP and EPSTI1 gene expression modulation in two different human breast cancer cell lines to suggest potential molecular mechanisms to unveil their role in the disease.

View Article: PubMed Central - PubMed

Affiliation: Joint IRB-BSC-CRG Program in Computational Biology, Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Catalonia, Spain.

ABSTRACT
A key element to delineate the biology of individual tumors is the regulation of apoptosis. In this work, we functionally characterize two breast cancer associated genes, the proteasome 26S subunit ATPase 3 interacting protein (PSMC3IP) and the epithelial-stromal interaction 1 (EPSTI1), to explore their potential apoptotic role in breast cancer. We first explore the existence of direct physical interactions with annotated BC-apoptotic genes. Based on the generated interaction network, we examine several apoptotic markers to determine the effect of PSMC3IP and EPSTI1 gene expression modulation in two different human breast cancer cell lines to suggest potential molecular mechanisms to unveil their role in the disease. Our results show that PSMC3IP and EPSTI1 are able to modulate the extrinsic apoptotic pathway in estrogen receptor positive and triple negative breast cancer cell lines, highlighting them as potential therapeutic targets.

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Mechanistic model of PSMC3IP and EPSTI1 as putative apoptotic factors.The extrinsic apoptosis pathway is initiated by the ligand binding to the death receptor, forming the DISC complex and leading to the activation of the caspase signaling cascade. The overexpression of EGFR and HER2 or activation of components of their downstream signaling pathways (i.e. PI3K pathway) induce an anti-apoptotic signaling through PI3K-Akt pathway in endocrine resistant breast cancer cells. Based on our findings, we suggest that PSMC3IP and EPSTI1 may regulate the apoptotic pathway via the physical interaction mainly with the apoptosis initiator CASP8, but also with AKT1 and BCAR3. Pro-apoptotic proteins are displayed in red and anti-apoptotic in green. Candidate proteins are displayed in purple.
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pone.0115352.g008: Mechanistic model of PSMC3IP and EPSTI1 as putative apoptotic factors.The extrinsic apoptosis pathway is initiated by the ligand binding to the death receptor, forming the DISC complex and leading to the activation of the caspase signaling cascade. The overexpression of EGFR and HER2 or activation of components of their downstream signaling pathways (i.e. PI3K pathway) induce an anti-apoptotic signaling through PI3K-Akt pathway in endocrine resistant breast cancer cells. Based on our findings, we suggest that PSMC3IP and EPSTI1 may regulate the apoptotic pathway via the physical interaction mainly with the apoptosis initiator CASP8, but also with AKT1 and BCAR3. Pro-apoptotic proteins are displayed in red and anti-apoptotic in green. Candidate proteins are displayed in purple.

Mentions: As shown in the summary Tables 1 and 2, collectively, our findings reveal that PSMC3IP and EPSTI1 have a strong anti-apoptotic role in breast cancer cells, particularly in estrogen receptor positive and triple negative, by means of physical interaction with the apoptosis initiator caspase-8 (Fig. 8). Interestingly, PSCM3IP or EPSTI1 depletion in breast cancer cells show increased DNA fragmentation and reduced cell viability even in the absence of apoptotic stimuli, indicating that they might also modulate the apoptotic pathway trough alternative mechanisms, such as by BCAR3 or AKT1 interaction, particularly in case of EPSTI1. Although further studies are required to gain deeper insight into the molecular mechanisms underlying the anti-apoptotic role of PSMC3IP and EPSTI1 in breast cancer, our findings highlight them beforehand as very interesting therapeutic targets, preeminently for their ability to apoptosis sensitization.


Breast cancer genes PSMC3IP and EPSTI1 play a role in apoptosis regulation.

Capdevila-Busquets E, Badiola N, Arroyo R, Alcalde V, Soler-López M, Aloy P - PLoS ONE (2015)

Mechanistic model of PSMC3IP and EPSTI1 as putative apoptotic factors.The extrinsic apoptosis pathway is initiated by the ligand binding to the death receptor, forming the DISC complex and leading to the activation of the caspase signaling cascade. The overexpression of EGFR and HER2 or activation of components of their downstream signaling pathways (i.e. PI3K pathway) induce an anti-apoptotic signaling through PI3K-Akt pathway in endocrine resistant breast cancer cells. Based on our findings, we suggest that PSMC3IP and EPSTI1 may regulate the apoptotic pathway via the physical interaction mainly with the apoptosis initiator CASP8, but also with AKT1 and BCAR3. Pro-apoptotic proteins are displayed in red and anti-apoptotic in green. Candidate proteins are displayed in purple.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4295872&req=5

pone.0115352.g008: Mechanistic model of PSMC3IP and EPSTI1 as putative apoptotic factors.The extrinsic apoptosis pathway is initiated by the ligand binding to the death receptor, forming the DISC complex and leading to the activation of the caspase signaling cascade. The overexpression of EGFR and HER2 or activation of components of their downstream signaling pathways (i.e. PI3K pathway) induce an anti-apoptotic signaling through PI3K-Akt pathway in endocrine resistant breast cancer cells. Based on our findings, we suggest that PSMC3IP and EPSTI1 may regulate the apoptotic pathway via the physical interaction mainly with the apoptosis initiator CASP8, but also with AKT1 and BCAR3. Pro-apoptotic proteins are displayed in red and anti-apoptotic in green. Candidate proteins are displayed in purple.
Mentions: As shown in the summary Tables 1 and 2, collectively, our findings reveal that PSMC3IP and EPSTI1 have a strong anti-apoptotic role in breast cancer cells, particularly in estrogen receptor positive and triple negative, by means of physical interaction with the apoptosis initiator caspase-8 (Fig. 8). Interestingly, PSCM3IP or EPSTI1 depletion in breast cancer cells show increased DNA fragmentation and reduced cell viability even in the absence of apoptotic stimuli, indicating that they might also modulate the apoptotic pathway trough alternative mechanisms, such as by BCAR3 or AKT1 interaction, particularly in case of EPSTI1. Although further studies are required to gain deeper insight into the molecular mechanisms underlying the anti-apoptotic role of PSMC3IP and EPSTI1 in breast cancer, our findings highlight them beforehand as very interesting therapeutic targets, preeminently for their ability to apoptosis sensitization.

Bottom Line: A key element to delineate the biology of individual tumors is the regulation of apoptosis.We first explore the existence of direct physical interactions with annotated BC-apoptotic genes.Based on the generated interaction network, we examine several apoptotic markers to determine the effect of PSMC3IP and EPSTI1 gene expression modulation in two different human breast cancer cell lines to suggest potential molecular mechanisms to unveil their role in the disease.

View Article: PubMed Central - PubMed

Affiliation: Joint IRB-BSC-CRG Program in Computational Biology, Institute for Research in Biomedicine (IRB Barcelona), Barcelona, Catalonia, Spain.

ABSTRACT
A key element to delineate the biology of individual tumors is the regulation of apoptosis. In this work, we functionally characterize two breast cancer associated genes, the proteasome 26S subunit ATPase 3 interacting protein (PSMC3IP) and the epithelial-stromal interaction 1 (EPSTI1), to explore their potential apoptotic role in breast cancer. We first explore the existence of direct physical interactions with annotated BC-apoptotic genes. Based on the generated interaction network, we examine several apoptotic markers to determine the effect of PSMC3IP and EPSTI1 gene expression modulation in two different human breast cancer cell lines to suggest potential molecular mechanisms to unveil their role in the disease. Our results show that PSMC3IP and EPSTI1 are able to modulate the extrinsic apoptotic pathway in estrogen receptor positive and triple negative breast cancer cell lines, highlighting them as potential therapeutic targets.

Show MeSH
Related in: MedlinePlus