{"doi":"10.1093/carcin/bgab126","title":"A Combination therapy using an mTOR inhibitor and Honokiol effectively induces autophagy through the modulation of AXL and Rubicon in renal cancer cells and restricts renal tumor growth following organ transplantation","abstract":"Development of cancer, including renal cancer, is a major problem in immunosuppressed patients. The mTOR inhibitor Rapamycin (RAPA) is used as an immunosuppressive agent in patients with organ transplants and other immunological disorders; and it also has antitumorigenic potential. However, long-term use of RAPA causes reactivation of Akt, and ultimately leads to enhanced tumor growth. Honokiol (HNK) is a natural compound, which possesses both anti-inflammatory and antitumorigenic properties. In this study, we investigated the effect of a novel combination therapy using RAPA + HNK on allograft survival and post-transplantation renal tumor growth. We observed that it effectively modulated the expression of some key regulatory molecules (like Carabin, an endogenous Ras inhibitor; and Rubicon, a negative regulator of autophagy) that play important roles in tumor cell growth and survival. This combination induced toxic autophagy and apoptosis to promote cancer cell death; and was associated with a reduced expression of the tumor-promoting receptor tyrosine kinase AXL. Finally, we utilized a novel murine model to examine the effect of RAPA + HNK on post-transplantation renal tumor growth. The combination treatment prolonged the allograft survival and significantly inhibited post-transplantation tumor growth. It was associated with reduced tumor expression of Rubicon and the cytoprotective/antioxidant heme oxygenase-1 to overcome therapeutic resistance. It also downregulated the coinhibitory programmed death-1 ligand, which plays major role(s) in the immune escape of tumor cells. Together, this combination treatment has a great potential to restrict renal tumor growth in transplant recipients as well as other immunosuppressed patients.","journal":"Carcinogenesis","year":2021,"id":182472,"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":15,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9533,"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":734868,"name":"Johannes Wedel","orcid":"0000-0002-3490-8477","position":1,"is_corresponding":false},{"id":734869,"name":"Kaifeng Liu","orcid":"0009-0003-0157-8349","position":2,"is_corresponding":false},{"id":412144,"name":"David Zurakowski","orcid":"0000-0003-3610-6942","position":3,"is_corresponding":false},{"id":366646,"name":"Samik Chakraborty","orcid":"0000-0002-5232-0474","position":4,"is_corresponding":false},{"id":482338,"name":"Evelyn Flynn","orcid":"0000-0003-1255-3844","position":5,"is_corresponding":false},{"id":734870,"name":"David M. Briscoe","orcid":"0000-0003-4135-5417","position":6,"is_corresponding":false},{"id":366648,"name":"Murugabaskar Balan","orcid":"0000-0002-5569-2273","position":7,"is_corresponding":false},{"id":366649,"name":"Soumitro Pal","orcid":"0000-0002-9177-6634","position":8,"is_corresponding":false},{"id":366645,"name":"Akash Sabarwal","orcid":"0000-0003-1760-4903","position":0,"is_corresponding":true}],"reference_count":53,"raw_metadata":null,"created_at":"2026-07-18T23:48:13.605421Z","pmid":"34965300","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":[]}