{"doi":"10.3390/cancers13092168","title":"PIK3C3 Inhibition Promotes Sensitivity to Colon Cancer Therapy by Inhibiting Cancer Stem Cells","abstract":"Background: Despite recent advances in therapies, resistance to chemotherapy remains a critical problem in the clinical management of colorectal cancer (CRC). Cancer stem cells (CSCs) play a central role in therapy resistance. Thus, elimination of CSCs is crucial for effective CRC therapy; however, such strategies are limited. Autophagy promotes resistance to cancer therapy; however, whether autophagy protects CSCs to promote resistance to CRC-therapy is not well understood. Moreover, specific and potent autophagy inhibitors are warranted as clinical trials with hydroxychloroquine have not been successful. Methods: Colon cancer cells and tumoroids were used. Fluorescent reporter-based analysis of autophagy flux, spheroid and side population (SP) culture, and qPCR were done. We synthesized 36-077, a potent inhibitor of PIK3C3/VPS34 kinase, to inhibit autophagy. Combination treatments were done using 5-fluorouracil (5-FU) and 36-077. Results: The 5-FU treatment induced autophagy only in a subset of the treated colon cancer. These autophagy-enriched cells also showed increased expression of CSC markers. Co-treatment with 36-077 significantly improved efficacy of the 5-FU treatment. Mechanistic studies revealed that combination therapy inhibited GSK-3β/Wnt/β-catenin signaling to inhibit CSC population. Conclusion: Autophagy promotes resistance to CRC-therapy by specifically promoting GSK-3β/Wnt/β-catenin signaling to promote CSC survival, and 36-077, a PIK3C3/VPS34 inhibitor, helps promote efficacy of CRC therapy.","journal":"Cancers","year":2021,"id":162889,"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":44,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9537,"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":268252,"name":"Rizwan Ahmad","orcid":"0000-0003-0331-6687","position":1,"is_corresponding":false},{"id":681356,"name":"Swagat Sharma","orcid":"0000-0002-4829-594X","position":2,"is_corresponding":false},{"id":681357,"name":"Saiprasad Gowrikumar","orcid":"0000-0002-9758-5425","position":3,"is_corresponding":false},{"id":681358,"name":"Mark Primeaux","orcid":"0000-0001-7589-3745","position":4,"is_corresponding":false},{"id":415308,"name":"Sandeep Rana","orcid":"0000-0001-5802-5970","position":5,"is_corresponding":false},{"id":415310,"name":"Amarnath Natarajan","orcid":"0000-0001-5067-0203","position":6,"is_corresponding":false},{"id":678518,"name":"David Oupický","orcid":"0000-0003-4710-861X","position":7,"is_corresponding":false},{"id":454817,"name":"Corey R. Hopkins","orcid":"0000-0003-4958-1697","position":8,"is_corresponding":false},{"id":664934,"name":"Punita Dhawan","orcid":"0000-0003-3434-8155","position":9,"is_corresponding":false},{"id":268254,"name":"Amar B. Singh","orcid":"0000-0003-1908-8594","position":10,"is_corresponding":false},{"id":681355,"name":"Balawant Kumar","orcid":"0000-0002-8187-3078","position":0,"is_corresponding":true}],"reference_count":63,"raw_metadata":null,"created_at":"2026-07-18T23:45:17.971865Z","pmid":"33946505","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":[]}