Inhibiting de novo lipogenesis identifies a therapeutic vulnerability in therapy-resistant colorectal cancer DOI Creative Commons
Eeshrita Jog, Ashwin Jainarayanan, Alessandro La Ferlita

и другие.

Redox Biology, Год журнала: 2024, Номер 79, С. 103458 - 103458

Опубликована: Дек. 11, 2024

A significant clinical challenge in patients with colorectal cancer (CRC), which adversely impacts patient survival, is the development of therapy resistance leading to a relapse. Therapy and relapse CRC associated formation lipid droplets (LD) by stimulating de novo lipogenesis (DNL). However, molecular mechanisms underlying increase DNL susceptibility DNL-targeted therapies remain unclear. Our study demonstrates that drug-tolerant persister cells (DTPs) over-express Lipin1 (LPIN1), facilitates sequestration free fatty acids into LDs. The increased expression mediated ETS1-PTPN1-c-Src-CEBPβ pathway. Blocking conversion LDs treatment statins or inhibiting lipin1 disrupts homeostasis, lipotoxicity ferroptotic cell death both DTPs patient-derived organoids (PDOs) vitro. Ferroptosis inhibitors N-acetylcysteine (NAC) can alleviate ROS resulting from inhibition. This strategy also significantly reduces tumor growth DTP mouse xenograft (PDX) models. findings highlight new metabolic vulnerability DTPs, PDO, PDX models provide framework for rational repurposing statins. Targeting phosphatidic acid (PA) diacylglycerol (DAG) prevent droplet could be an effective therapeutic approach therapy-resistant CRC.

Язык: Английский

Inhibiting de novo lipogenesis identifies a therapeutic vulnerability in therapy-resistant colorectal cancer DOI Creative Commons
Eeshrita Jog, Ashwin Jainarayanan, Alessandro La Ferlita

и другие.

Redox Biology, Год журнала: 2024, Номер 79, С. 103458 - 103458

Опубликована: Дек. 11, 2024

A significant clinical challenge in patients with colorectal cancer (CRC), which adversely impacts patient survival, is the development of therapy resistance leading to a relapse. Therapy and relapse CRC associated formation lipid droplets (LD) by stimulating de novo lipogenesis (DNL). However, molecular mechanisms underlying increase DNL susceptibility DNL-targeted therapies remain unclear. Our study demonstrates that drug-tolerant persister cells (DTPs) over-express Lipin1 (LPIN1), facilitates sequestration free fatty acids into LDs. The increased expression mediated ETS1-PTPN1-c-Src-CEBPβ pathway. Blocking conversion LDs treatment statins or inhibiting lipin1 disrupts homeostasis, lipotoxicity ferroptotic cell death both DTPs patient-derived organoids (PDOs) vitro. Ferroptosis inhibitors N-acetylcysteine (NAC) can alleviate ROS resulting from inhibition. This strategy also significantly reduces tumor growth DTP mouse xenograft (PDX) models. findings highlight new metabolic vulnerability DTPs, PDO, PDX models provide framework for rational repurposing statins. Targeting phosphatidic acid (PA) diacylglycerol (DAG) prevent droplet could be an effective therapeutic approach therapy-resistant CRC.

Язык: Английский

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