Inhibition of Mitochondrial Dynamics Preferentially Targets Pancreatic Cancer Cells with Enhanced Tumorigenic and Invasive Potential

Courtois, Sarah; Luxán-Delgado, Beatriz de; Penin-Peyta, Laure; Royo-García, Alba; Parejo-Alonso, Beatriz; Jagušt, Petra; Alcalá, Sonia; Rubiolo, Juan A.; Sánchez, Laura; Sáinz, Bruno; Heeschen, Christopher; Sancho, Patricia

doi:10.3390/cancers13040698

Cited by 39 publications

(28 citation statements)

References 45 publications

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“…Divided mitochondria exhibit dot-like and fragmentary features. This dynamic process participates in tumor heterogeneity, promotes the malignant phenotype, accelerates tumor progression and invasion, and affects treatment and prognosis ( 16 , 17 ). Mitochondrial fission is thought to be a multi-step and complex process ( Table 1 ).…”

Section: Mitochondrial Dynamics and Cancersmentioning

confidence: 99%

Mitochondria-Shaping Proteins and Chemotherapy

et al. 2021

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The emergence, in recent decades, of an entirely new area of “Mitochondrial dynamics”, which consists principally of fission and fusion, reflects the recognition that mitochondria play a significant role in human tumorigenesis and response to therapeutics. Proteins that determine mitochondrial dynamics are referred to as “shaping proteins”. Marked heterogeneity has been observed in the response of tumor cells to chemotherapy, which is associated with imbalances in mitochondrial dynamics and function leading to adaptive and acquired resistance to chemotherapeutic agents. Therefore, targeting mitochondria-shaping proteins may prove to be a promising approach to treat chemotherapy resistant cancers. In this review, we summarize the alterations of mitochondrial dynamics in chemotherapeutic processing and the antitumor mechanisms by which chemotherapy drugs synergize with mitochondria-shaping proteins. These might shed light on new biomarkers for better prediction of cancer chemosensitivity and contribute to the exploitation of potent therapeutic strategies for the clinical treatment of cancers.

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Section: Mitochondrial Dynamics and Cancersmentioning

confidence: 99%

Mitochondria-Shaping Proteins and Chemotherapy

et al. 2021

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“…The functional impact of mitochondrial morphology on metabolic output has proven to be highly context dependent. For example, mitochondrial fission drives increased oxidative mitochondrial metabolism and tumorigenic potential in pancreatic ductal adenocarcinoma cells 39,40 and decreased oxidative mitochondrial metabolism in neuroblastoma cells 41 . Future work is needed to understand how mitochondrial elongation enables prostate cancer cells to better survive AR blockade.…”

Section: Discussionmentioning

confidence: 99%

Androgen receptor inhibition induces metabolic reprogramming and increased reliance on oxidative mitochondrial metabolism in prostate cancer

Crowell

Giafaglione

Jones

et al. 2022

Preprint

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Prostate cancer cells that survive clinical androgen receptor (AR) blockade mediate disease progression and lethality. Reprogrammed metabolic signaling is one mechanism by which tumor cells can survive treatment. However, how AR inhibition reprograms metabolism, and whether altered metabolism can be exploited to eradicate cells that survive AR blockade, remains unclear. Here, we comprehensively characterized the effect of AR blockade on prostate cancer metabolism using transcriptomics, metabolomics, and bioenergetics approaches. AR inhibition maintains oxidative mitochondrial metabolism and reduces glycolytic signaling, through hexokinase II downregulation and decreased MYC activity. Robust elongation of mitochondria via reduced DRP1 activity supports cell fitness after AR blockade. In addition, AR inhibition enhances sensitivity to complex I inhibitors in several models, suggesting that AR blockade increases reliance on oxidative mitochondrial metabolism. Our study provides an enhanced understanding of how AR inhibition alters metabolic signaling and highlights the potential of therapies that target metabolic vulnerabilities in AR-inhibited cells.

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“…Pancreatic adenocarcinoma patient-derived xenograft models (PDXs) 354 and 185 were obtained from the Biobank of the Spanish National Cancer Research Centre (CNIO), Madrid, Spain (references B18230PDX7, B18243PDX4). Cells were isolated from these tumors and established for in vitro culture as described elsewhere …”

Section: Methodsmentioning

confidence: 99%

Smart Nanoparticles as Advanced Anti-Akt Kinase Delivery Systems for Pancreatic Cancer Therapy

González‐Valdivieso

García-Sampedro

Hall

et al. 2021

ACS Appl. Mater. Interfaces

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Pancreatic cancer is one of the deadliest cancers partly due to late diagnosis, poor drug delivery to the target site, and acquired resistance to therapy. Therefore, more effective therapies are urgently needed to improve the outcome of patients. In this work, we have tested self-assembling genetically engineered polymeric nanoparticles formed by elastin-like recombinamers (ELRs), carrying a small peptide inhibitor of the protein kinase Akt, in both PANC-1 and patient-derived pancreatic cancer cells (PDX models). Nanoparticle cell uptake was measured by flow cytometry, and subcellular localization was determined by confocal microscopy, which showed a lysosomal localization of these nanoparticles. Furthermore, metabolic activity and cell viability were significantly reduced after incubation with nanoparticles carrying the Akt inhibitor in a time-and dose-dependent fashion. Self-assembling 73 ± 3.2 nm size nanoparticles inhibited phosphorylation and consequent activation of Akt protein, blocked the NF-κB signaling pathway, and triggered caspase 3-mediated apoptosis. Furthermore, in vivo assays showed that ELR-based nanoparticles were suitable devices for drug delivery purposes with long circulating time and minimum toxicity. Hence, the use of these smart nanoparticles could lead to the development of more effective treatment options for pancreatic cancer based on the inhibition of Akt.

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Inhibition of Mitochondrial Dynamics Preferentially Targets Pancreatic Cancer Cells with Enhanced Tumorigenic and Invasive Potential

Cited by 39 publications

References 45 publications

Mitochondria-Shaping Proteins and Chemotherapy

Mitochondria-Shaping Proteins and Chemotherapy

Androgen receptor inhibition induces metabolic reprogramming and increased reliance on oxidative mitochondrial metabolism in prostate cancer

Smart Nanoparticles as Advanced Anti-Akt Kinase Delivery Systems for Pancreatic Cancer Therapy

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