A Human Ribonuclease Variant and ERK-Pathway Inhibitors Exhibit Highly Synergistic Toxicity for Cancer Cells
Pancreatic-type ribonucleases (ptRNases) are prevalent secretory enzymes that catalyze the cleavage of RNA. Ribonuclease inhibitor (RI) is a cytosolic protein that has femtomolar affinity for ptRNases, affording protection from the toxic catalytic activity of ptRNases, which can invade human cells....
| Main Authors: | , , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | English |
| Published: |
American Association for Cancer Research (AACR)
2020
|
| Online Access: | https://hdl.handle.net/1721.1/123520 |
| _version_ | 1826195900520726528 |
|---|---|
| author | Hoang, Trish T. Tanrikulu, Ismet Caglar Vatland, Quinn A. Hoang, Trieu M. Raines, Ronald T |
| author2 | Massachusetts Institute of Technology. Department of Chemistry |
| author_facet | Massachusetts Institute of Technology. Department of Chemistry Hoang, Trish T. Tanrikulu, Ismet Caglar Vatland, Quinn A. Hoang, Trieu M. Raines, Ronald T |
| author_sort | Hoang, Trish T. |
| collection | MIT |
| description | Pancreatic-type ribonucleases (ptRNases) are prevalent secretory enzymes that catalyze the cleavage of RNA. Ribonuclease inhibitor (RI) is a cytosolic protein that has femtomolar affinity for ptRNases, affording protection from the toxic catalytic activity of ptRNases, which can invade human cells. A human ptRNase variant that is resistant to inhibition by RI is a cytotoxin that is undergoing a clinical trial as a cancer chemotherapeutic agent. We find that the ptRNase and protein kinases in the ERK pathway exhibit strongly synergistic toxicity toward lung cancer cells (including a KRAS[superscript G12C] variant) and melanoma cells (including BRAF[superscript V600E] variants). The synergism arises from inhibiting the phosphorylation of RI and thereby diminishing its affinity for the ptRNase. These findings link seemingly unrelated cellular processes, and suggest that the use of a kinase inhibitor to unleash a cytotoxic enzyme could lead to beneficial manifestations in the clinic. |
| first_indexed | 2024-09-23T10:17:37Z |
| format | Article |
| id | mit-1721.1/123520 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T10:17:37Z |
| publishDate | 2020 |
| publisher | American Association for Cancer Research (AACR) |
| record_format | dspace |
| spelling | mit-1721.1/1235202022-09-30T20:10:19Z A Human Ribonuclease Variant and ERK-Pathway Inhibitors Exhibit Highly Synergistic Toxicity for Cancer Cells Hoang, Trish T. Tanrikulu, Ismet Caglar Vatland, Quinn A. Hoang, Trieu M. Raines, Ronald T Massachusetts Institute of Technology. Department of Chemistry Pancreatic-type ribonucleases (ptRNases) are prevalent secretory enzymes that catalyze the cleavage of RNA. Ribonuclease inhibitor (RI) is a cytosolic protein that has femtomolar affinity for ptRNases, affording protection from the toxic catalytic activity of ptRNases, which can invade human cells. A human ptRNase variant that is resistant to inhibition by RI is a cytotoxin that is undergoing a clinical trial as a cancer chemotherapeutic agent. We find that the ptRNase and protein kinases in the ERK pathway exhibit strongly synergistic toxicity toward lung cancer cells (including a KRAS[superscript G12C] variant) and melanoma cells (including BRAF[superscript V600E] variants). The synergism arises from inhibiting the phosphorylation of RI and thereby diminishing its affinity for the ptRNase. These findings link seemingly unrelated cellular processes, and suggest that the use of a kinase inhibitor to unleash a cytotoxic enzyme could lead to beneficial manifestations in the clinic. National Institutes of Health (U.S.) (Grant R01 CA073808) 2020-01-22T15:52:37Z 2020-01-22T15:52:37Z 2018-12 2020-01-06T18:23:32Z Article http://purl.org/eprint/type/JournalArticle 1535-7163 1538-8514 https://hdl.handle.net/1721.1/123520 Hoang, Trish T. et al. "A Human Ribonuclease Variant and ERK-Pathway Inhibitors Exhibit Highly Synergistic Toxicity for Cancer Cells." Molecular Cancer Therapeutics 17, 12 (December 2018): 2622–2632 © 2018 American Association for Cancer Research en http://dx.doi.org/10.1158/1535-7163.mct-18-0724 Molecular Cancer Therapeutics Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf American Association for Cancer Research (AACR) PMC |
| spellingShingle | Hoang, Trish T. Tanrikulu, Ismet Caglar Vatland, Quinn A. Hoang, Trieu M. Raines, Ronald T A Human Ribonuclease Variant and ERK-Pathway Inhibitors Exhibit Highly Synergistic Toxicity for Cancer Cells |
| title | A Human Ribonuclease Variant and ERK-Pathway Inhibitors Exhibit Highly Synergistic Toxicity for Cancer Cells |
| title_full | A Human Ribonuclease Variant and ERK-Pathway Inhibitors Exhibit Highly Synergistic Toxicity for Cancer Cells |
| title_fullStr | A Human Ribonuclease Variant and ERK-Pathway Inhibitors Exhibit Highly Synergistic Toxicity for Cancer Cells |
| title_full_unstemmed | A Human Ribonuclease Variant and ERK-Pathway Inhibitors Exhibit Highly Synergistic Toxicity for Cancer Cells |
| title_short | A Human Ribonuclease Variant and ERK-Pathway Inhibitors Exhibit Highly Synergistic Toxicity for Cancer Cells |
| title_sort | human ribonuclease variant and erk pathway inhibitors exhibit highly synergistic toxicity for cancer cells |
| url | https://hdl.handle.net/1721.1/123520 |
| work_keys_str_mv | AT hoangtrisht ahumanribonucleasevariantanderkpathwayinhibitorsexhibithighlysynergistictoxicityforcancercells AT tanrikuluismetcaglar ahumanribonucleasevariantanderkpathwayinhibitorsexhibithighlysynergistictoxicityforcancercells AT vatlandquinna ahumanribonucleasevariantanderkpathwayinhibitorsexhibithighlysynergistictoxicityforcancercells AT hoangtrieum ahumanribonucleasevariantanderkpathwayinhibitorsexhibithighlysynergistictoxicityforcancercells AT rainesronaldt ahumanribonucleasevariantanderkpathwayinhibitorsexhibithighlysynergistictoxicityforcancercells AT hoangtrisht humanribonucleasevariantanderkpathwayinhibitorsexhibithighlysynergistictoxicityforcancercells AT tanrikuluismetcaglar humanribonucleasevariantanderkpathwayinhibitorsexhibithighlysynergistictoxicityforcancercells AT vatlandquinna humanribonucleasevariantanderkpathwayinhibitorsexhibithighlysynergistictoxicityforcancercells AT hoangtrieum humanribonucleasevariantanderkpathwayinhibitorsexhibithighlysynergistictoxicityforcancercells AT rainesronaldt humanribonucleasevariantanderkpathwayinhibitorsexhibithighlysynergistictoxicityforcancercells |