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Targeting TGF-β–Smad2/3–JNK1-mediated SIRT1 activity overcomes the chemoresistance of KRAS mutation lung cancer

Dongcheon Shin,Min-Gew Choi,Chungyong Han,Sang Soo Kim

Published 2025 in Experimental and Molecular Medicine

ABSTRACT

Patients with lung cancer harboring a KRAS oncogenic driver mutation have a very poor prognosis. Recently, we reported that SIRT1 is upregulated by the KRASMut–c-Myc axis, and that KRASMut-induced SIRT1 is stably deacetylated at lysine 104, which in turn increases KRASMut activity and enhances chemoresistance. Notably, SIRT1 activity as well as SIRT1 levels are more elevated in KRASMut cells compared with EGFRMut, KRASMut- and EGFRMut-negative cells, and nontumorigenic cells. This prompted us to investigate the mechanism by which SIRT1 activity was increased and the role of pSIRT1 in the chemoresistance of KRASMut lung cancer cells. The activated MEK–ERK pathway under KRASMut increased AP-1 transcription activity, which in turn enhanced TGF-β1 secretion. The secreted TGF-β1 activated the Smad2/3–JNK1 signaling pathway in an autocrine manner, increasing pSIRT1S27 and pSIRT1S47, ultimately enhancing KRASMut activity through KRAS deacetylation and affecting chemoresistance. We identified a small molecule from the natural compound library—Kuwanon C (KWN-C), a SIRT1 activity inhibitor—which reduced pSIRT1S27 and pSIRT1S47 levels via a decrease in the activity of the TGF-β1–-Smad2/3–JNK1 signaling pathway. Treatment with the SIRT1 activity inhibitor triggered the anticancer effects of cisplatin and pemetrexed in human lung cancer cells, lung orthotopic tumors and a spontaneous in vivo model of KRASMut lung cancer. Our findings reveal a novel pathway critical for the regulation of SIRT1 activity in KRASMut lung cancer and provide important evidence for the potential application of SIRT1 activity inhibitors as an adjuvant chemotherapy, overcoming chemoresistance in patients with KRASMut lung cancer. Mutations in the KRAS gene are common in several cancers, including lung cancer, and make treatment challenging. Researchers explore a new approach by focusing on a protein called SIRT1, which is found at higher levels in KRAS-mutated lung cancer cells. They used various laboratory techniques to study how SIRT1 interacts with KRAS mutations. They discovered that SIRT1 helps KRAS mutations become more active, which contributes to cancer growth and resistance to chemotherapy. By using natural compounds to inhibit SIRT1 activity, they found that they could make cancer cells more sensitive to existing chemotherapy drugs. The study suggests that targeting SIRT1 could be a promising strategy to improve treatment for patients with KRAS-mutated lung cancer. They propose that combining SIRT1 inhibitors with current chemotherapy could enhance treatment effectiveness and reduce drug resistance. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.

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