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The role of regulation and subcellular localization of GTP biosynthesis in melanoma invasion and metastasis

GTP生物合成的调控和亚细胞定位在黑色素瘤侵袭和转移中的作用

基本信息

批准号：
10636058
负责人：
Mikhail Nikiforov
金额：
$ 55.52万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-30 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10636058
关键词：
Anabolism Automobile Driving Biogenesis Biology Blood - brain barrier anatomy Cell membrane Cells Cephalic Chemicals Clinic Co-Immunoprecipitations Communication Data Data Reporting Dependence Disease model Dissociation Dose Enzymes Event Gene Expression Gene Expression Profiling Genetic Transcription Goals Guanosine Triphosphate IMPDH2 gene Immune response Immunosuppressive Agents Immunotherapy Inosine Monophosphate Invaded Link Lipids MAP Kinase Gene Melanoma Cell Membrane Membrane Microdomains Messenger RNA Metabolism Metastatic Melanoma Metastatic malignant neoplasm to brain Methods Modification Mus Mutagenesis Mutation Nature Neoplasm Metastasis Oxidoreductase PI3K/AKT Paper Pathway interactions Patients Penetration Pharmaceutical Preparations Phenotype Physiological Plasma Cells Play Pre-Clinical Model Prognosis Proliferating Protein Analysis Proteinase 3 Proteins Radiosurgery Regulation Reporting Ribavirin Role STAT3 gene Signal Transduction Site Skin Cancer Sun Exposure Testing Transactivation Transcriptional Activation Tumor Escape Tumorigenicity Up-Regulation anti-hepatitis C anti-tumor immune response clinically relevant curative treatments effective therapy efficacy testing enzyme biosynthesis gene expression database inhibitor melanoma mouse model mycophenolate mofetil novel novel strategies programmed cell death ligand 1 programs protein transport recruit rho GTP-Binding Proteins transcription factor treatment strategy

项目摘要

Metastatic melanoma is the most aggressive type of skin cancer with no treatment. Acquisition of invasive phenotypes is a critical event driving progression from primary to metastatic melanoma which is most detrimental for patient survival in THE case of melanoma brain metastases (MBMs). Invasion of melanoma cells depends on activation of several RHO-GTPases which regulate the biogenesis of cell protrusions. Among RHO-GTPases, RAC1 plays the most prominent role in melanoma progression. Indeed, P29S activating mutation of RAC1 (detected predominately in melanoma) is the 3rd most common mutation in sun-exposed melanomas. In addition, RAC1 and other RHO-GTPases function as effectors and/or regulators of signal transduction programs activated in MBMs, including MAPK, PI3K/AKT or STAT3 pathways. However, mechanisms regulating RHO-GTPase activity in melanoma in general or in MBMs are understudied. Physiological changes of intracellular GTP have not been thought to regulate RHO-GTPase activity because total GTP levels in the cell were considered to be much higher than GTP dissociation constant of RHO proteins (KdRHO•GTP). In our papers (Bianchi-Smiraglia et al. Nature Methods 2017 & Nature Communications 2021; Wolff et al, Cell Chemical Biology 2022), we demonstrated that not only free GTP levels comparable to KdRHO•GTP existed in the cell, but also that RAC1 activation depended on availability of local free GTP. Furthermore, RAC1 interacted with inosine monophosphate dehydrogenase 2 (IMPDH2, a rate limiting enzyme in GTP biosynthesis) and, through this interaction, with other GTP metabolism enzymes (GMEs). Accordingly, IMPDH2 and GMEs were enriched together with RAC1 in cell protrusions of invading cells. Disruption of IMPDH2-RAC1 interaction via sequestration of IMPDH2 away from the plasma membrane did not alter total GTP pools, but decreased local GTP levels in cell protrusions, RAC1 activity, and cell invasion. IMPDH2 and other GTP metabolism enzymes do not contain membrane localization sequences, however, do associate with the plasma membrane. We also demonstrated that high IMPDH2 levels correlate with poor prognosis in melanoma patients. Thus, in the 1st Specific Aim we will establish the mechanisms that recruit IMPDH2 to plasma membrane and cell protrusions. In the 2nd Specific Aim, we will identify and characterize mechanisms maintaining high IMPDH2 levels in metastatic melanoma cells. In the 3rd Specific Aim, we will interrogate the inhibition of IMPDH2 as a novel strategy for treatment of MBMs.

转移性黑色素瘤是最具侵袭性的皮肤癌，没有治疗方法。侵入性获取