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Phosphorylated TLR3 nuclear translocation in cancer cell promotes metastasis and chemoresistance

ABSTRACT: Phosphorylated TLR3 nuclear translocation in cancer cell promotes metastasis and chemoresistance

ORGANISM(S): Homo Sapiens

SUBMITTER: Zixin Wang

PROVIDER: PXD064767 | iProX | Sat Jun 07 00:00:00 BST 2025

REPOSITORIES: iProX

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Phosphorylated Toll-like receptor 3 nuclear translocation in cancer cell promotes metastasis and chemoresistance.

Wang Zixin Z Gu Yan Y Liu Yanfang Y Wang Ziqiao Z Chen Xinyuan X Wang Haoze H Zhang Wei W Jin Gang G Cao Xuetao X

Signal transduction and targeted therapy 20250718 1

Aberrant expression and subcellular location of innate sensors in cancer cells, such as Toll-like receptors (TLRs), correlates with pro-tumoral inflammation and cancer progression, but the mechanism is still largely unknown. Deciphering the proinflammatory mediators in tumor microenvironment will contribute to the development of cancer therapeutics. By using immunohistochemistry in pancreatic ductal adenocarcinoma (PDAC) and multiple other cancer samples, here we found that cancer cell TLR3, a w ...[more]

PMID: 40675966

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Phosphorylated TLR3 nuclear translocation in cancer cell promotes metastasis and chemoresistance

Project description:Phosphorylated TLR3 nuclear translocation in cancer cell promotes metastasis and chemoresistance

| PRJNA1272840 | ENA

Phosphorylated TLR3 nuclear translocation in cancer cell promotes metastasis and chemoresistance

Project description:Aberrant expression and subcellular location of innate sensors in cancer cells, such as Toll-like receptors (TLRs), correlates with pro-tumoral inflammation and cancer progression, but the mechanism is still largely unknown. Deciphering the proinflammatory mediators in tumor microenvironment will contribute to the development of cancer therapeutics. By using immunohistochemistry in pancreatic ductal adenocarcinoma (PDAC) and multiple other cancer samples, here we found that cancer cell TLR3, a well-known cytoplasmic dsRNA sensor, translocated to the nucleus especially upon chemotherapy stress. Nuclear TLR3 increased the invasive and proliferative properties, and inhibited chemotherapy-induced apoptosis of cancer cells in vitro. Meanwhile, mice bearing cancer cells with nuclear TLR3 exhibited increased liver metastasis and shortened survival. Mechanistically, phosphokinase JAK1 was responsible for TLR3 phosphorylation at S155 to induce its nuclear translocation in cooperation with a nuclear transport factor importin α5. Chemotherapeutic stress induced the aberrant aggregation of dsRNA in the nucleus, which potentially contributed to nuclear TLR3 activation. Then nuclear TLR3 recruited protein arginine methyltransferase 5 (PRMT5) and bound to c-Myc to promote symmetrical dimethylation and multimerization of c-Myc, resulting in the activation of c-Myc downstream target genes and pro-tumoral signaling pathways. Accordingly, high levels of cancer cell nuclear TLR3 in clinical samples predicted patients’ worse prognosis with shorter disease-free survival, overall survival and poor response to neoadjuvant chemotherapy. Therefore, the identification of nuclear TLR3 provides new insight into non-classical functions of innate immune sensors in cancer, and JAK1/TLR3/PRMT5/c-Myc axis may sever as a new prognostic indicator and potential therapeutic target to overcome chemoresistance.

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Nuclear accumulation of ADAMTS1 zymogen: A novel mechanism promoting chemoresistance and metastasis in breast cancer

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Nuclear accumulation of ADAMTS1 zymogen: A novel mechanism promoting chemoresistance and metastasis in breast cancer [RNA-Seq]

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TFAM loss induces nuclear actin assembly upon mDia2 malonylation to promote liver cancer metastasis

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2022-07-26 | GSE189459 | GEO

Targeted dephosphorylation of TFEB promotes its nuclear translocation

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Targeted dephosphorylation of TFEB promotes its nuclear translocation

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Nucleus-Translocated GCLM Promotes Chemoresistance in Colorectal Cancer through a Moonlighting Function

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2024-11-15 | PXD055376 | Pride

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