{"doi":"10.1101/2021.07.21.453259","title":"Sensitization of FOLFOX-resistant colorectal cancer cells via the modulation of a novel pathway involving protein phosphatase 2A","abstract":"SUMMARY The treatment of colorectal cancer (CRC) with FOLFOX shows some efficacy, but these tumors quickly develop resistance to this treatment. We have observed an increased phosphorylation of AKT1/mTOR/4EBP1 and levels of p21 in FOLFOX-resistant CRC cells. We have identified a small molecule, NSC49L, that stimulates protein phosphatase 2A (PP2A) activity, downregulates the AKT1/mTOR/4EBP1-axis, and inhibits p21 translation. We have provided evidence that NSC49L- and TRAIL-mediated sensitization is synergistically induced in p21-knockdown CRC cells, which is reversed in p21-overexpressing cells. p21 binds with procaspase 3 and prevents activation of caspase 3. We have shown that TRAIL induces apoptosis through the activation of caspase 3 by NSC49L-mediated downregulation of p21 translation, and thereby cleavage of procaspase 3 into caspase 3. NSC49L does not affect global protein synthesis. These studies provide a mechanistic understanding of NSC49L as a PP2A agonist, and how its combination with TRAIL sensitizes FOLFOX-resistant CRC cells. Graphical Abstract","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":221307,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9578,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":374081,"name":"Asif Raza","orcid":"0000-0002-5716-7202","position":1,"is_corresponding":false},{"id":313914,"name":"Iqbal Mahmud","orcid":"0000-0001-7729-8122","position":2,"is_corresponding":false},{"id":821325,"name":"Nayeong Koo","orcid":"0000-0002-1860-2574","position":3,"is_corresponding":false},{"id":294955,"name":"Timothy J. Garrett","orcid":"0000-0003-1623-009X","position":4,"is_corresponding":false},{"id":813096,"name":"Mary E. Law","orcid":"0000-0002-6625-0534","position":5,"is_corresponding":false},{"id":719736,"name":"Brian K. Law","orcid":"0000-0002-8411-6531","position":6,"is_corresponding":false},{"id":249225,"name":"Arun Sharma","orcid":"0000-0002-7679-7779","position":7,"is_corresponding":false},{"id":821324,"name":"Satya Narayan","orcid":"0000-0001-7080-8900","position":0,"is_corresponding":true}],"reference_count":92,"raw_metadata":null,"created_at":"2026-07-18T23:53:55.215284Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}