Activation of MAP Kinase Pathway by Polyisoprenylated Cysteinyl Amide Inhibitors Causes Apoptosis and Disrupts Breast Cancer Cell Invasion
Prognoses for TNBC remain poor due to its aggressive nature and the lack of therapies that target its “drivers”. RASA1, a RAS-GAP or GTPase-activating protein whose activity inhibits RAS signaling, is downregulated in up to 77% of TNBC cases. As such, RAS proteins become hyperactive and similar in e...
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| Format: | Article |
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MDPI AG
2024-02-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/12/3/470 |
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| author | Jassy Mary S. Lazarte Nazarius S. Lamango |
| author_facet | Jassy Mary S. Lazarte Nazarius S. Lamango |
| author_sort | Jassy Mary S. Lazarte |
| collection | DOAJ |
| description | Prognoses for TNBC remain poor due to its aggressive nature and the lack of therapies that target its “drivers”. RASA1, a RAS-GAP or GTPase-activating protein whose activity inhibits RAS signaling, is downregulated in up to 77% of TNBC cases. As such, RAS proteins become hyperactive and similar in effect to mutant hyperactive RAS proteins with impaired GTPase activities. PCAIs are a novel class of agents designed to target and disrupt the activities of KRAS and other G-proteins that are hyperactive in various cancers. This study shows the anticancer mechanisms of the PCAIs in two breast cancer cell lines, MDA-MB-468 and MDA-MB-231. PCAIs (NSL-YHJ-2-27) treatment increased BRAF phosphorylation, whereas CRAF phosphorylation significantly decreased in both cell lines. Moreover, the PCAIs also stimulated the phosphorylation of MEK, ERK, and p90RSK by 116, 340, and 240% in MDA-MB-468 cells, respectively. However, in MDA-MB-231 cells, a significant increase of 105% was observed only in p90RSK phosphorylation. Opposing effects were observed for AKT phosphorylation, whereby an increase was detected in MDA-MB-468 cells and a decrease in MDA-MB-231 cells. The PCAIs also induced apoptosis, as observed in the increased pro-apoptotic protein BAK1, by 51%, after treatment. The proportion of live cells in PCAIs-treated spheroids decreased by 42 and 34% in MDA-MB-468 and MDA-MB-231 cells, respectively, which further explains the PCAIs-induced apoptosis. The movement of the cells through the Matrigel was also inhibited by 74% after PCAIs exposure, which could have been due to the depleted levels of F-actin and vinculin punctate, resulting in the shrinkage of the cells by 76%, thereby impeding cell movement. These results show promise for PCAIs as potential therapies for TNBC as they significantly inhibit the hallmark processes and pathways that promote cell proliferation, migration, and invasion, which result in poor prognoses for breast cancer patients. |
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| language | English |
| last_indexed | 2024-04-24T18:32:09Z |
| publishDate | 2024-02-01 |
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| series | Biomedicines |
| spelling | doaj.art-425c69fe24d54a579397c334c8434bcf2024-03-27T13:22:26ZengMDPI AGBiomedicines2227-90592024-02-0112347010.3390/biomedicines12030470Activation of MAP Kinase Pathway by Polyisoprenylated Cysteinyl Amide Inhibitors Causes Apoptosis and Disrupts Breast Cancer Cell InvasionJassy Mary S. Lazarte0Nazarius S. Lamango1College of Pharmacy Pharmaceutical Sciences, Institute of Public Health, Florida A&M University, Tallahassee, FL 32307, USACollege of Pharmacy Pharmaceutical Sciences, Institute of Public Health, Florida A&M University, Tallahassee, FL 32307, USAPrognoses for TNBC remain poor due to its aggressive nature and the lack of therapies that target its “drivers”. RASA1, a RAS-GAP or GTPase-activating protein whose activity inhibits RAS signaling, is downregulated in up to 77% of TNBC cases. As such, RAS proteins become hyperactive and similar in effect to mutant hyperactive RAS proteins with impaired GTPase activities. PCAIs are a novel class of agents designed to target and disrupt the activities of KRAS and other G-proteins that are hyperactive in various cancers. This study shows the anticancer mechanisms of the PCAIs in two breast cancer cell lines, MDA-MB-468 and MDA-MB-231. PCAIs (NSL-YHJ-2-27) treatment increased BRAF phosphorylation, whereas CRAF phosphorylation significantly decreased in both cell lines. Moreover, the PCAIs also stimulated the phosphorylation of MEK, ERK, and p90RSK by 116, 340, and 240% in MDA-MB-468 cells, respectively. However, in MDA-MB-231 cells, a significant increase of 105% was observed only in p90RSK phosphorylation. Opposing effects were observed for AKT phosphorylation, whereby an increase was detected in MDA-MB-468 cells and a decrease in MDA-MB-231 cells. The PCAIs also induced apoptosis, as observed in the increased pro-apoptotic protein BAK1, by 51%, after treatment. The proportion of live cells in PCAIs-treated spheroids decreased by 42 and 34% in MDA-MB-468 and MDA-MB-231 cells, respectively, which further explains the PCAIs-induced apoptosis. The movement of the cells through the Matrigel was also inhibited by 74% after PCAIs exposure, which could have been due to the depleted levels of F-actin and vinculin punctate, resulting in the shrinkage of the cells by 76%, thereby impeding cell movement. These results show promise for PCAIs as potential therapies for TNBC as they significantly inhibit the hallmark processes and pathways that promote cell proliferation, migration, and invasion, which result in poor prognoses for breast cancer patients.https://www.mdpi.com/2227-9059/12/3/470polyisoprenylated cysteinyl amide inhibitors (PCAIs)breast cancerTNBCmitogen-activated protein kinase (MAPK) signaling pathwayapoptosiscell invasion |
| spellingShingle | Jassy Mary S. Lazarte Nazarius S. Lamango Activation of MAP Kinase Pathway by Polyisoprenylated Cysteinyl Amide Inhibitors Causes Apoptosis and Disrupts Breast Cancer Cell Invasion Biomedicines polyisoprenylated cysteinyl amide inhibitors (PCAIs) breast cancer TNBC mitogen-activated protein kinase (MAPK) signaling pathway apoptosis cell invasion |
| title | Activation of MAP Kinase Pathway by Polyisoprenylated Cysteinyl Amide Inhibitors Causes Apoptosis and Disrupts Breast Cancer Cell Invasion |
| title_full | Activation of MAP Kinase Pathway by Polyisoprenylated Cysteinyl Amide Inhibitors Causes Apoptosis and Disrupts Breast Cancer Cell Invasion |
| title_fullStr | Activation of MAP Kinase Pathway by Polyisoprenylated Cysteinyl Amide Inhibitors Causes Apoptosis and Disrupts Breast Cancer Cell Invasion |
| title_full_unstemmed | Activation of MAP Kinase Pathway by Polyisoprenylated Cysteinyl Amide Inhibitors Causes Apoptosis and Disrupts Breast Cancer Cell Invasion |
| title_short | Activation of MAP Kinase Pathway by Polyisoprenylated Cysteinyl Amide Inhibitors Causes Apoptosis and Disrupts Breast Cancer Cell Invasion |
| title_sort | activation of map kinase pathway by polyisoprenylated cysteinyl amide inhibitors causes apoptosis and disrupts breast cancer cell invasion |
| topic | polyisoprenylated cysteinyl amide inhibitors (PCAIs) breast cancer TNBC mitogen-activated protein kinase (MAPK) signaling pathway apoptosis cell invasion |
| url | https://www.mdpi.com/2227-9059/12/3/470 |
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