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Mitochondrial signatures shape phenotype switching and apoptosis in response to PLK1 and RSK inhibitiors in melanoma

ABSTRACT: Mitochondrial signatures shape phenotype switching and apoptosis in response to PLK1 and RSK inhibitiors in melanoma

PROVIDER: PRJNA1103800 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28782507.fastq.gz	Fastqsanger.gz
	SRR28782508.fastq.gz	Fastqsanger.gz
	SRR28782509.fastq.gz	Fastqsanger.gz
	SRR28782510.fastq.gz	Fastqsanger.gz
	SRR28782511.fastq.gz	Fastqsanger.gz

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Mitochondrial signatures shape phenotype switching and apoptosis in response to PLK1 and RSK inhibitiors in melanoma

Project description:PLK1 inhibitors are emerging anti-cancer agents being tested in monotherapy and combination therapies for various cancers. Although PLK1 inhibition in experimental models shows potent antitumor effects, translation to the clinic has been hampered by low antitumor activity and tumor relapse. Here, we report the identification of mitochondrial protein signatures that determine sensitivity to approaches targeting PLK1 in human melanoma cell lines. In response to PLK1 inhibition or gene silencing, resistant cells adopt a pro-inflammatory and dedifferentiated phenotype, while sensitive cells engage apoptosis. Mitochondrial DNA depletion and silencing of the ABCD1 transporter sensitize cells to PLK1 inhibition and attenuate the associated pro-inflammatory response. We also found that non-selective inhibitors of the p90 ribosomal S6 kinase (RSK) exert their anti-proliferative and pro-inflammatory effects via PLK1 inhibition. This work reveals overlooked impacts of PLK1 on phenotype switching and suggests that mitochondrial precision medicine can help improve response to targeted therapies.

2024-06-14 | GSE264686 | GEO

Mitochondrial signatures shape phenotype switching and apoptosis in response to PLK1 inhibitors.

Project description:PLK1 inhibitors are emerging anticancer agents that are being tested as monotherapy and combination therapies for various cancers. Although PLK1 inhibition in experimental models has shown potent antitumor effects, translation to the clinic has been hampered by low antitumor activity and tumor relapse. Here, we report the identification of mitochondrial protein signatures that determine the sensitivity to approaches targeting PLK1 in human melanoma cell lines. In response to PLK1 inhibition or gene silencing, resistant cells adopt a pro-inflammatory and dedifferentiated phenotype, whereas sensitive cells undergo apoptosis. Mitochondrial DNA depletion and silencing of the ABCD1 transporter sensitize cells to PLK1 inhibition and attenuate the associated pro-inflammatory response. We also found that nonselective inhibitors of the p90 ribosomal S6 kinase (RSK) exert their antiproliferative and pro-inflammatory effects via PLK1 inhibition. Specific inhibition of RSK, on the other hand, is anti-inflammatory and promotes a program of antigen presentation. This study reveals the overlooked effects of PLK1 on phenotype switching and suggests that mitochondrial precision medicine can help improve the response to targeted therapies.

| S-EPMC11632064 | biostudies-literature

PLK1 inhibition selectively induces apoptosis in ARID1A deficient cells through uncoupling of oxygen consumption from ATP production

Project description:Inhibitors of the mitotic kinase PLK1 yield objective responses in a subset of refractory cancers. However, PLK1 overexpression in cancer does not correlate with drug sensitivity, and the clinical development of PLK1 inhibitors has been hampered by the lack of patient selection marker. Using a high-throughput chemical screen, we discovered that cells deficient for the tumor suppressor ARID1A are highly sensitive to PLK1 inhibition. Interestingly this sensitivity was unrelated to canonical functions of PLK1 in mediating G2-M cell cycle transition. Instead, a whole-genome CRISPR screen revealed PLK1 inhibitor sensitivity in ARID1A deficient cells to be dependent on the mitochondrial translation machinery. We find that ARID1A knock-out (KO) cells have an unusual mitochondrial phenotype with aberrant biogenesis, increased oxygen consumption/ expression of oxidative phosphorylation genes, but without increased ATP production. Using expansion microscopy and biochemical fractionation, we see that a subset of PLK1 localizes to the mitochondria in interphase cells. Inhibition of PLK1 in ARID1A KO cells further uncouples oxygen consumption from ATP production, with subsequent membrane depolarization and apoptosis. Knockdown of specific subunits of the mitochondrial ribosome reverses PLK1-inhibitor induced apoptosis in ARID1A deficient cells, confirming specificity of the phenotype. Together, these findings highlight a novel interphase role for PLK1 in maintaining mitochondrial fitness under metabolic stress, and a strategy for therapeutic use of PLK1 inhibitors. To translate these findings, we describe a quantitative microscopy assay for assessment of ARID1A protein loss, which could offer a novel patient selection strategy for the clinical development of PLK1 inhibitors in cancer.

2022-03-08 | PXD031110 | Pride

Vascular smooth muscle cell phenotype switching during cancer progression.

Project description:Vascular smooth muscle cell phenotype switching during cancer progression.

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Cuspal shape alterations by Bmp4 directing cell proliferation and apoptosis

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Centrosomal Localization of DNAJ-PKAc Fusion Heightens PLK1 Inhibitor Sensitivity in Fibrolamellar Cancer

Project description:Fibrolamellar carcinoma (FLC), a rare and fatal liver cancer lacking effective drug therapy, is driven by the DNAJ-PKAc fusion oncoprotein. However, the underlying mechanism of DNAJ-PKAc's role in FLC tumor growth remains enigmatic. Employing an unbiased systems-based approach, we uncovered a new role of DNAJ-PKAc oncoprotein in FLC and identified downstream kinases involved in this process. Functional screening, coupled with computational analysis, highlighted Polo-like kinase 1 (PLK1) as vital for FLC cell viability. Genetic and pharmacological PLK1 inhibition significantly reduced FLC cell growth, inducing apoptosis. Further studies showed DNAJ-PKAc's centrosomal presence and direct interaction with PLK1, revealing a novel mechanism that promotes PLK1 activation and mitotic progression. Clinical-grade PLK1 inhibitors effectively suppressed FLC tumor growth across multiple preclinical models, including patient-derived xenograft and an orthotopic model of FLC, suggesting promising therapeutic avenues. Our findings underscore the role of DNAJ-PKAc in rewiring signaling networks and highlight valuable clinical implications for PLK1-targeted therapies for FLC.

2023-12-19 | GSE250059 | GEO

Dystrophin Deficiency Derives Phenotype Switching in Vascular Smooth Muscle Cells

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Expression profile in Plk1(+/-) aortas

Project description:Transcriptional profiling of mouse aortas comparing control wild-type animals with aortas from three different Plk1(+/-) mice. Goal was to determine the effects of Plk1 haploinsufficiency in aorta expression profiles.

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Hierarchy of TGFβ/SMAD, Hippo/YAP/TAZ and Wnt/β-catenin signaling in melanoma phenotype switching

Project description:In melanoma, a switch from a proliferative melanocytic to an invasive mesenchymal phenotype is based on dramatic transcriptional reprogramming which involves complex interactions between a variety of signaling pathways and their downstream transcriptional regulators. TGFb/SMAD, Hippo/YAP/TAZ and Wnt/b-catenin signaling pathways are major inducers of transcriptional reprogramming and converge at several levels. Here, we report that TGFb/SMAD, YAP/TAZ and b-catenin are all required for a proliferative-to-invasive phenotype switch. Loss and gain of function experimentation, global gene expression analysis, and computational nested effects models revealed the hierarchy between these signaling pathways and identified shared target genes. SMAD-mediated transcription at the top of the hierarchy leads to the activation of YAP/TAZ and of b-catenin, with YAP/TAZ governing an essential sub-program of TGFb-induced phenotype switching. Wnt/b-catenin signaling is situated further downstream and exerts a dual role: it promotes the proliferative, differentiated melanoma cell phenotype and it is essential but not sufficient for SMAD or YAP/TAZ-induced phenotype switching. The results identify epistatic interactions among the signaling pathways underlying melanoma phenotype switching and highlight the priorities in targets for melanoma therapy.

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An epigenetic gene signature underlies phenotype switching in early stage melanomas.

Project description:An epigenetic gene signature underlies phenotype switching in early stage melanomas.

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