RESUMO
Oxaliplatin has been included as a basal drug in various chemotherapy regimens for colorectal cancer (CRC), a global health concern. However, acquired resistance to oxaliplatin affects the prognosis. This study aimed to determine whether the consumption of a KD increases the sensitivity of CRC cells to oxaliplatin via the inhibition of a classical stem cell marker, Krupple-like factor 5 (KLF5). KLF5 functions as a transcription factor for the leukemia inhibitory factor (LIF) and directly binds to its promoter region. LIF upregulation induces dephosphorylation of metal regulatory transcription factor 1 (MTF1), which is recruited to the promoter area of Ferroportin (FPN1), the only cellular iron exporter. FPN1 upregulation reduces the labile iron pool (LIP) and ferroptosis in CRC cells. KLF5 knockdown inhibits the LIF/MTF1/FPN1 axis and induces iron overload, thereby conferring sensitivity to oxaliplatin to CRC cells. KD mimicked KLF5 silencing and sensitized CRC cells to oxaliplatin via a similar mechanism. Thus, potential correlations were observed among ketogenesis, stemness, and iron homeostasis. This finding can be used to formulate a new strategy for overcoming oxaliplatin resistance in patients with CRC.
Assuntos
Proteínas de Transporte de Cátions , Neoplasias Colorretais , Resistencia a Medicamentos Antineoplásicos , Homeostase , Ferro , Fatores de Transcrição Kruppel-Like , Fator Inibidor de Leucemia , Oxaliplatina , Humanos , Oxaliplatina/farmacologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Fatores de Transcrição Kruppel-Like/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Ferro/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Proteínas de Transporte de Cátions/genética , Homeostase/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Fator Inibidor de Leucemia/metabolismo , Fator Inibidor de Leucemia/genética , Ferroptose/efeitos dos fármacos , Ferroptose/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Antineoplásicos/farmacologia , AnimaisRESUMO
Aflatoxin B1 (AFB1), a potential endocrine disrupter, has been shown to induce hepatotoxicity in animal models, but the effects of AFB1 on Leydig cell function are unclear. In this study, in vivo exposure to AFB1 at 15 and 150⯵g/kg/day lowered serum testosterone (T), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) levels, reduced Leydig cell number, and down-regulated the expression of testosterone biosynthesis-related genes. In vitro study showed that AFB1 (10⯵M) significantly increased ROS levels, and decreased T production in Leydig cells by suppressing certain T-biosynthesis gene expressions. Moreover, AFB1 induced Leydig cell apoptosis through lowering pAMPK/AMPK ratio and increasing pmTOR/mTOR ratio, and then further up-regulating autophagy and apoptosis proteins, LC3, BECLIN 1, and BAX, as well as down-regulating autophagy flux protein P62 and anti-apoptosis protein BCL-2. AFB1-induced toxicity in Leydig cells was characterized by inhibiting T-biosynthesis gene expression, reducing Leydig cell number, promoting ROS production, and inducing cell apoptosis via suppressing AMPK/mTOR-mediated autophagy flux pathway.