{"doi":"10.1093/carcin/bgac031","title":"Suppressing the activation of protein kinase A as a DNA damage-independent mechanistic lead for dihydromethysticin prophylaxis of NNK-induced lung carcinogenesis","abstract":"Our earlier work demonstrated varying potency of dihydromethysticin (DHM) as the active kava phytochemical for prophylaxis of tobacco carcinogen nicotine-derived nitrosamine ketone (NNK)-induced mouse lung carcinogenesis. Efficacy was dependent on timing of DHM gavage ahead of NNK insult. In addition to DNA adducts in the lung tissues mitigated by DHM in a time-dependent manner, our in vivo data strongly implicated the existence of DNA damage-independent mechanism(s) in NNK-induced lung carcinogenesis targeted by DHM to fully exert its anti-initiation efficacy. In the present work, RNA seq transcriptomic profiling of NNK-exposed (2 h) lung tissues with/without a DHM (8 h) pretreatment revealed a snap shot of canonical acute phase tissue damage and stress response signaling pathways as well as an activation of protein kinase A (PKA) pathway induced by NNK and the restraining effects of DHM. The activation of the PKA pathway by NNK active metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) at a concentration incapable of promoting DNA adduct was confirmed in a lung cancer cell culture model, potentially through NNAL binding to and activation of the β-adrenergic receptor. Our in vitro and in vivo data overall support the hypothesis that DHM suppresses PKA activation as a key DNA damage-independent mechanistic lead, contributing to its effective prophylaxis of NNK-induced lung carcinogenesis. Systems biology approaches with a detailed temporal dissection of timing of DHM intake versus NNK exposure are warranted to fill the knowledge gaps concerning the DNA damage-driven mechanisms and DNA damage-independent mechanisms to optimize the implementation strategy for DHM to achieve maximal lung cancer chemoprevention.","journal":"Carcinogenesis","year":2022,"id":271587,"datarank":0.38474240361923057,"base_score":2.5649493574615367,"endowment":2.5649493574615367,"self_citation_contribution":0.38474240361923057,"citation_network_contribution":0.0,"self_endowment_contribution":0.38474240361923057,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":12,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9458,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":695449,"name":"Haocheng Ding","orcid":"0000-0003-1379-7824","position":1,"is_corresponding":false},{"id":236488,"name":"Yuzhi Wang","orcid":"0000-0003-3552-1589","position":2,"is_corresponding":false},{"id":380431,"name":"Qi Hu","orcid":"0000-0002-7876-2705","position":3,"is_corresponding":false},{"id":258510,"name":"Sixue Chen","orcid":"0000-0002-6690-7612","position":4,"is_corresponding":false},{"id":353746,"name":"Naomi Fujioka","orcid":"0000-0003-3277-6754","position":5,"is_corresponding":false},{"id":741022,"name":"Fatima Zahra Aly","orcid":"0000-0002-1738-339X","position":6,"is_corresponding":false},{"id":298329,"name":"Junxuan Lü","orcid":"0000-0002-2354-7186","position":7,"is_corresponding":false},{"id":270104,"name":"Zhiguang Huo","orcid":"0000-0002-8032-4392","position":8,"is_corresponding":false},{"id":298331,"name":"Chengguo Xing","orcid":"0000-0002-4266-6236","position":9,"is_corresponding":false},{"id":298326,"name":"Tengfei Bian","orcid":"0000-0002-4029-2576","position":0,"is_corresponding":true}],"reference_count":67,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:27:39.717534Z","pmid":"35353881","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":[]}