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Targeting the mevalonate pathway potentiates NUAK1 inhibition-induced immunogenic cell death and antitumor immunity

ABSTRACT: Targeting the mevalonate pathway potentiates NUAK1 inhibition-induced immunogenic cell death and antitumor immunity

PROVIDER: PRJNA1196347 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR31665689_1.fastq.gz	Fastqsanger.gz
	SRR31665689_2.fastq.gz	Fastqsanger.gz
	SRR31665690_1.fastq.gz	Fastqsanger.gz
	SRR31665690_2.fastq.gz	Fastqsanger.gz

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Targeting the mevalonate pathway potentiates NUAK1 inhibition-induced immunogenic cell death and antitumor immunity

Project description:The induction of immunogenic cell death (ICD) impedes tumor progression via both tumor cell-intrinsic and -extrinsic mechanisms, representing a robust therapeutic strategy. However, there remains a dearth of ICD-inducing targets. Employing kinome-wide CRISPR-Cas9 screening, we have identified NUAK1 as a potential target. The ICD-provoking effect of NUAK1 inhibition depends on the production of reactive oxygen species (ROS), consequent to the downregulation of NRF2-mediated antioxidant gene expression. Moreover, the mevalonate pathway/cholesterol biosynthesis, activated by XBP1s downstream of NUAK1 inhibition-induced endoplasmic reticulum stress, functions as negative feedback on ICD. Targeting the mevalonate pathway using HMGCR inhibitor statins amplifies NUAK1 inhibition-mediated ICD and antitumor activity, while cholesterol mitigates ICD by diminishing ROS. The combination of NUAK1 inhibitors and statins enhances the efficacy of anti-PD-1 therapy. Collectively, our study unveils the promise of blocking the mevalonate pathway in conjunction with ICD-targeted immunotherapies such as NUAK1 inhibition.

2024-12-10 | GSE264513 | GEO

Targeting the mevalonate pathway potentiates NUAK1 inhibition-induced immunogenic cell death and antitumor immunity

Project description:The induction of immunogenic cell death (ICD) impedes tumor progression via both tumor cell-intrinsic and -extrinsic mechanisms, representing a robust therapeutic strategy. However, ICD-targeted therapy remains to be explored and optimized. Through kinome-wide CRISPR-Cas9 screen, NUAK1 is identified as a potential target. The ICD-provoking effect of NUAK1 inhibition depends on the production of reactive oxygen species (ROS), consequent to the downregulation of NRF2-mediated antioxidant gene expression. Moreover, the mevalonate pathway/cholesterol biosynthesis, activated by XBP1s downstream of ICD-induced endoplasmic reticulum stress, functions as a negative feedback mechanism. Targeting the mevalonate pathway with CRISPR knockout or HMGCR inhibitor simvastatin amplifies NUAK1 inhibition-mediated ICD and antitumor activity, while cholesterol dampers ROS, ICD and therefore tumor suppression. The combination of NUAK1 inhibitor and statin enhances the efficacy of anti-PD-1 therapy. Collectively, our study unveils the promise of blocking the mevalonate-cholesterol pathway in conjunction with ICD-targeted immunotherapy.

2024-12-11 | GSE283933 | GEO

Targeting the mevalonate pathway potentiates NUAK1 inhibition-induced immunogenic cell death and antitumor immunity

Project description:Targeting the mevalonate pathway potentiates NUAK1 inhibition-induced immunogenic cell death and antitumor immunity

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Colorectal tumors require NUAK1 for protection from oxidative stress

Project description:NUAK1 is a member of the AMPK family of kinases involved in regulation of cell adhesion, metabolism and stress responses. Our previous analysis revealed a requirement for NUAK1 to sustain viability when MYC is overexpressed. Human colorectal cancer (CRC) shows near uniform overexpression of MYC, suggesting that this cancer may be particularly amenable to NUAK1 inhibition. This work reveals that elevated NUAK1 expression in human CRC correlates with more aggressive disease, lymph node metastasis and reduced overall survival. Deletion of Nuak1 in murine intestines prevented outgrowth of colonic tumors driven by loss of Apc and KRas mutation, while depletion of Nuak1 in pre-existing tumors drove rapid tumor regression. Mechanistically, we show that NUAK1 promotes anti-oxidant gene expression by facilitating nuclear import of NRF2. Deletion or inhibition of NUAK1 renders cells vulnerable to oxidative stress and provision of exogenous anti-oxidants protects cells in culture and colonic tumors in situ from Nuak1 depletion.

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Local inhibition of protein phosphatase 1 by NUAK1 promotes spliceosome assembly and reveals a MYC-sensitive feedback control of transcriptional elongation

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