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

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.