Similar articles

Abstract: carbonyl reductase 1 (CBR1), a member of the short-chain dehydrogenase/reductase (SDR) superfamily, is implicated in tumor progression and treatment resistance. However, its role in non-small cell lung cancer (NSCLC) remains unclear. This study examined CBR1 expression in NSCLC tissues and cell lines, using gene interference and pharmacological inhibition to assess its impact on stemness, chemosensitivity, and quiescence, and to explore underlying mechanisms. Our findings indicate that CBR1 expression is elevated in NSCLC tissues and cell lines, and further increases in the presence of cisplatin (CDDP). Gene interference reducing CBR1 expression significantly decreased the percentage of cluster of differentiation 133 (CD133)-positive cells and the expression of octamer-binding transcription factor 4 (OCT4) and SRY (sex determining region Y)-box 2 (SOX2), while enhancing CDDP chemosensitivity. The CBR1-specific inhibitor hydroxy-PP-Me (PP-Me) markedly increased CDDP cytotoxicity and reduced stemness. Additionally, CBR1 inhibition via short hairpin RNA (shRNA) CBR1 (sh-CBR1) or PP-Me disrupted NSCLC cell quiescence, as shown by a decrease in G0 phase cells and p27 expression, alongside an increase in cyclin D1 and phospho-retinoblastoma (pRb) expression. Furthermore, SET domain-containing protein 4 (SETD4), which mediates stemness, chemosensitivity, and quiescence in NSCLC cells, was downregulated by sh-CBR1 or PP-Me treatment. The overexpression of SETD4 counteracted the enhanced chemosensitivity resulting from CBR1 inhibition. In A549 xenografts, combined PP-Me and CDDP therapy significantly inhibited tumor growth compared to either treatment alone. In conclusion, CBR1 inhibition enhances CDDP chemosensitivity by suppressing stemness and quiescence in NSCLC.

CBR1通过调节细胞干性和静止状态介导非小细胞肺癌化疗敏感性

[1]BrayJE, MarsdenBD, OppermannU, 2009. The human short-chain dehydrogenase/reductase (SDR) superfamily: a bioinformatics summary. Chem Biol Interact, 178(1-3):99-109.

[2]BrodyH, 2020. Lung cancer. Nature, 587(7834):S7.

[3]CaiSL, YangYS, DingYF, et al., 2022. SETD4 cells contribute to brain development and maintain adult stem cell reservoir for neurogenesis. Stem Cell Reports, 17(9):2081-2096.

[4]ChenG, ZhangHH, SunHX, et al., 2023a. Bufalin targeting BFAR inhibits the occurrence and metastasis of gastric cancer through PI3K/AKT/mTOR signal pathway. Apoptosis, 28(9-10):1390-1405.

[5]ChenG, YangLN, LiuGX, et al., 2023b. Research progress in protein microarrays: focussing on cancer research. Proteom Clin Appl, 17(1):2200036.

[6]ChenKC, ZhangCZ, LingSB, et al., 2021. The metabolic flexibility of quiescent CSC: implications for chemotherapy resistance. Cell Death Discov, 12(9):835.

[7]DaiL, YeS, LiHW, et al., 2017. SETD4 regulates cell quiescence and catalyzes the trimethylation of H4K20 during diapause formation in Artemia. Mol Cell Biol, 37(7):e00453-16.

[8]GalluzziL, SenovillaL, VitaleI, et al., 2012. Molecular mechanisms of cisplatin resistance. Oncogene, 31(15):1869-1883.

[9]HengWS, GosensR, KruytFAE, 2019. Lung cancer stem cells: origin, features, maintenance mechanisms and therapeutic targeting. Biochem Pharmacol, 160:121-133.

[10]HerzHM, GarrussA, ShilatifardA, 2013. SET for life: biochemical activities and biological functions of SET domain-containing proteins. Trends Biochem Sci, 38(12):621-639.

[11]IwamotoY, MitsudomiT, SakaiK, et al., 2015. Randomized phase II study of adjuvant chemotherapy with long-term S-1 versus cisplatin+S-1 in completely resected stage II-IIIA non-small cell lung cancer. Clin Cancer Res, 21(23):5245-5252.

[12]JangM, KimY, WonH, et al., 2012. Carbonyl reductase 1 offers a novel therapeutic target to enhance leukemia treatment by arsenic trioxide. Cancer Res, 72(16):4214-4224.

[13]JiangX, LiY, FengJL, et al., 2020. Safrana l prevents prostate cancer recurrence by blocking the re-activation of quiescent cancer cells via downregulation of S-phase kinase-associated protein 2. Front Cell Dev Biol, 8:598620.

[14]JoA, ChoiTG, JoYH, et al., 2017. Inhibition of carbonyl reductase 1 safely improves the efficacy of doxorubicin in breast cancer treatment. Antioxid Redox Sign, 26(2):70-83.

[15]KalabusJL, ChengQY, JamilRG, et al., 2012. Induction of carbonyl reductase 1 (CBR1) expression in human lung tissues and lung cancer cells by the cigarette smoke constituent benzo[a]pyrene. Toxicol Lett, 211(3):266-273.

[16]KavanaghKL, JörnvallH, PerssonB, et al., 2008. Medium- and short-chain dehydrogenase/reductase gene and protein families: the SDR superfamily: functional and structural diversity within a family of metabolic and regulatory enzymes. Cell Mol Life Sci, 65(24):3895.

[17]Koczurkiewicz-AdamczykP, PiskaK, Gunia-KrzyżakA, et al., 2020. Cinnamic acid derivatives as chemosensitising agents against DOX-treated lung cancer cells ‒ involvement of carbonyl reductase 1. Eur J Pharm Sci, 154:105511.

[18]Koczurkiewicz-AdamczykP, GąsiorkiewiczB, PiskaK, et al., 2022. Cinnamamide derivatives with 4-hydroxypiperidine moiety enhance effect of doxorubicin to cancer cells and protect cardiomyocytes against drug-induced toxicity through CBR1 inhibition mechanism. Life Sci, 305:120777.

[19]LalS, SandanarajE, WongZW, et al., 2008. CBR1 and CBR3 pharmacogenetics and their influence on doxorubicin disposition in Asian breast cancer patients. Cancer Sci, 99(10):2045-2054.

[20]LiaoXM, WuCX, ShaoZM, et al., 2021. SETD4 in the proliferation, migration, angiogenesis, myogenic differentiation and genomic methylation of bone marrow mesenchymal stem cells. Stem Cell Rev Rep, 17(4):1374-1389.

[21]MasseyAJ, BenwellK, BurbridgeM, et al., 2021. Targeting DYRK1A/B kinases to modulate p21-cyclin D1-p27 signalling and induce anti-tumour activity in a model of human glioblastoma. J Cell Mol Med, 25(22):10650-10662.

[22]MatsunagaT, KezukaC, MorikawaY, et al., 2015. Up-regulation of carbonyl reductase 1 renders development of doxorubicin resistance in human gastrointestinal cancers. Biol Pharm Bull, 38(9):1309-1319.

[23]MillerM, HannaN, 2021. Advances in systemic therapy for non-small cell lung cancer. BMJ, 375:n2363.

[24]Morin-BuoteJ, Ennour-IdrissiK, PoirierÉ, et al., 2021. Association of breast tumour expression of cannabinoid receptors CBR1 and CBR2 with prognostic factors and survival in breast cancer patients. J Pers Med, 11(9):852.

[25]MukhopadhyayD, GoelHL, XiongCA, et al., 2023. The calcium channel TRPC6 promotes chemotherapy-induced persistence by regulating integrin α6 mRNA splicing. Cell Rep, 42(11):113347.

[26]MurakamiA, YakabeK, YoshidomiK, et al., 2012. Decreased carbonyl reductase 1 expression promotes malignant behaviours by induction of epithelial mesenchymal transition and its clinical significance. Cancer Lett, 323(1):69-76.

[27]NihoS, YoshidaT, AkimotoT, et al., 2020. Randomized phase II study of chemoradiotherapy with cisplatin + S-1 versus cisplatin + pemetrexed for locally advanced non-squamous non-small cell lung cancer: SPECTRA study. Lung Cancer, 141:64-71.

[28]OppermannU, 2007. Carbonyl reductases: the complex relationships of mammalian carbonyl- and quinone-reducing enzymes and their role in physiology. Annu Rev Pharmacol Toxicol, 47(1):293-322.

[29]OsawaY, YokoyamaY, ShigetoT, et al., 2015. Decreased expression of carbonyl reductase 1 promotes ovarian cancer growth and proliferation. Int J Oncol, 46(3):1252-1258.

[30]PennycookBR, BarrAR, 2020. Restriction point regulation at the crossroads between quiescence and cell proliferation. FEBS Lett, 594(13):2046-2060.

[31]PiskaK, KoczurkiewiczP, WnukD, et al., 2019. Synergistic anticancer activity of doxorubicin and piperlongumine on DU-145 prostate cancer cells ‒ the involvement of carbonyl reductase 1 inhibition. Chem Biol Interact, 300:40-48.

[32]SchlagerJJ, PowisG, 1990. Cytosolic NAD(P)H:(Quinone-acceptor)oxidoreductase in human normal and tumor tissue: effects of cigarette smoking and alcohol. Int J Cancer, 45(3):403-409.

[33]ShiSM, DiL, 2017. The role of carbonyl reductase 1 in drug discovery and development. Expert Opin Drug Metab Toxicol, 13(8):859-870.

[34]SiegelRL, MillerKD, FuchsHE, et al., 2021. Cancer statistics, 2021. CA A Cancer J Clin, 71(1):7-33.

[35]TakE, LeeS, LeeJ, et al., 2011. Human carbonyl reductase 1 upregulated by hypoxia renders resistance to apoptosis in hepatocellular carcinoma cells. J Hepatol, 54(2):328-339.

[36]WangYH, YuYM, YangWJ, et al., 2023. SETD4 confers cancer stem cell chemoresistance in nonsmall cell lung cancer patients via the epigenetic regulation of cellular quiescence. Stem Cells Int, 2023:7367854.

[37]YeS, DingYF, JiaWH, et al., 2019. SET domain-containing protein 4 epigenetically controls breast cancer stem cell quiescence. Cancer Res, 79(18):4729-4743.

[38]ZhangHH, ZhangZ, GuoTT, et al., 2023a. Annexin A protein family: focusing on the occurrence, progression and treatment of cancer. Front Cell Dev Biol, 11:1141331.

[39]ZhangHH, DongXL, DingXY, et al., 2023b. Bufalin targeting CAMKK2 inhibits the occurrence and development of intrahepatic cholangiocarcinoma through Wnt/β-catenin signal pathway. J Transl Med, 21:900.

[40]ZhangYJ, ZhangHX, ZhangXL, et al., 2022. CBR3-AS1 accelerates the malignant proliferation of gestational choriocarcinoma cells by stabilizing SETD4. Dis Markers, 2022:7155525.

[41]ZhongYY, YeP, MeiZZ, et al., 2019. The novel methyltransferase SETD4 regulates TLR agonist-induced expression of cytokines through methylation of lysine 4 at histone 3 in macrophages. Mol Immunol, 114:179-188.

[42]ZhouL, YangC, ZhongWL, et al., 2021. Chrysin induces autophagy-dependent ferroptosis to increase chemosensitivity to gemcitabine by targeting CBR1 in pancreatic cancer cells. Biochem Pharmacol, 193:114813.

[43]ZhuSX, XuYP, SongM, et al., 2016. PRDM16 is associated with evasion of apoptosis by prostatic cancer cells according to RNA interference screening. Mol Med Rep, 14(4):3357-3361.