P-cadherin induces anoikis-resistance of matrix-detached breast cancer cells by promoting pentose phosphate pathway and decreasing oxidative stress

Sousa, Bárbara; Pereira, Joana; Marques, Ricardo; Grilo, Luís F.; Pereira, Susana P.; Sardão, Vilma A.; Schmitt, Fernando; Oliveira, Paulo J.; Paredes, Joana

doi:10.1016/j.bbadis.2020.165964

Cited by 31 publications

(22 citation statements)

References 49 publications

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“…However pretreating cells with quercetin (an antioxidant) ameliorated tunicamycin induced stress and cytoxicity by impairing CHOP expression and normalizing antioxidant property [37]. Here, we report depletion in antioxidant genes expression following stress induction and pro-apoptotic UPR effects of metformin, which support previous reports that antioxidants activity enhanced anoikis resistance [31][32][33]73].…”

Section: Supplementary Materialssupporting

confidence: 89%

“…We proceeded to check K48 ubiquitin aggregation in metformin-treated cells and observed accumulation of misfolded protein in the metformin-treated group compared to the control (Figure 3G). Previous studies revealed superoxide dismutase (an antioxidant) activity facilitated anoikis resistance in ECM detached cancer cells [31][32][33], so we sought to investigate the effect of metformin treatment on two antioxidant families glutathione peroxidase 1-3 and superoxide dismutase 1-3 (Figure 3H). Our result showed metformin treatment significantly alleviated superoxide dismutase and glutathione peroxidase levels in tumor cells thus sensitizing these cells to anoikis.…”

Section: Metformin Abrogates Upregulated Proteasome Activity In Ecm D...mentioning

confidence: 99%

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Targeting Oxidative Phosphorylation-Proteasome Activity in Extracellular Detached Cells Promotes Anoikis and Inhibits Metastasis

Adeshakin

Liu

Cheng

et al. 2021

Life

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Metastasis arises owing to tumor cells’ capacity to evade pro-apoptotic signals. Anoikis—the apoptosis of detached cells (from the extracellular matrix (ECM)) is often circumvented by metastatic cells as a result of biochemical and molecular transformations. These facilitate cells’ ability to survive, invade and reattach to secondary sites. Here, we identified deregulated glucose metabolism, oxidative phosphorylation, and proteasome in anchorage-independent cells compared to adherent cells. Metformin an anti-diabetic drug that reduces blood glucose (also known to inhibit mitochondrial Complex I), and proteasome inhibitors were employed to target these changes. Metformin or proteasome inhibitors alone increased misfolded protein accumulation, sensitized tumor cells to anoikis, and impaired pulmonary metastasis in the B16F10 melanoma model. Mechanistically, metformin reduced cellular ATP production, activated AMPK to foster pro-apoptotic unfolded protein response (UPR) through enhanced expression of CHOP in ECM detached cells. Furthermore, AMPK inhibition reduced misfolded protein accumulation, thus highlight relevance of AMPK activation in facilitating metformin-induced stress and UPR cell death. Our findings provide insights into the molecular biology of anoikis resistance and identified metformin and proteasome inhibitors as potential therapeutic options for tumor metastasis.

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Section: Supplementary Materialssupporting

confidence: 89%

Section: Metformin Abrogates Upregulated Proteasome Activity In Ecm D...mentioning

confidence: 99%

Targeting Oxidative Phosphorylation-Proteasome Activity in Extracellular Detached Cells Promotes Anoikis and Inhibits Metastasis

Adeshakin

Liu

Cheng

et al. 2021

Life

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“…Normal cells require adherence to the extracellular matrix to survive. Cell shedding leads to a dramatic increase in reactive oxygen species (ROS), which promotes anoikis [ 45 , 46 ]. Mammary epithelial cells can reduce anoikis by increasing mitochondrial antioxidant enzyme SOD2 to reduce ROS produced by mitochondrial glucose oxidation [ 47 ].…”

Section: Discussionmentioning

confidence: 99%

A Bioinformatics-Based Analysis of an Anoikis-Related Gene Signature Predicts the Prognosis of Patients with Low-Grade Gliomas

Zhao

Chi

et al. 2022

Brain Sciences

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Low-grade glioma (LGG) is a highly aggressive disease in the skull. On the other hand, anoikis, a specific form of cell death induced by the loss of cell contact with the extracellular matrix, plays a key role in cancer metastasis. In this study, anoikis-related genes (ANRGs) were used to identify LGG subtypes and to construct a prognostic model for LGG patients. In addition, we explored the immune microenvironment and enrichment pathways between different subtypes. We constructed an anoikis-related gene signature using the TCGA (The Cancer Genome Atlas) cohort and investigated the differences between different risk groups in clinical features, mutational landscape, immune cell infiltration (ICI), etc. Kaplan–Meier analysis showed that the characteristics of ANRGs in the high-risk group were associated with poor prognosis in LGG patients. The risk score was identified as an independent prognostic factor. The high-risk group had higher ICI, tumor mutation load (TMB), immune checkpoint gene expression, and therapeutic response to immune checkpoint blockers (ICB). Functional analysis showed that these high-risk and low-risk groups had different immune statuses and drug sensitivity. Risk scores were used together with LGG clinicopathological features to construct a nomogram, and Decision Curve Analysis (DCA) showed that the model could enable patients to benefit from clinical treatment strategies.

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“…Thus, targeting oxidation pathways could be promising for developing immune therapies for breast cancer. Studies have shown that the spread of BC metastatic cells and their survival in circulation depends on different factors, including antioxidant protection [ 117 ]. The oxidative stress response is used by breast cancer cells to adapt to their nutrient-poor environment [ 118 ].…”

Section: Resultsmentioning

confidence: 99%

Drug Repositioning and Subgroup Discovery for Precision Medicine Implementation in Triple Negative Breast Cancer

Al-Taie

Hannink

Mitchem

et al. 2021

Cancers

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Breast cancer (BC) is the leading cause of death among female patients with cancer. Patients with triple-negative breast cancer (TNBC) have the lowest survival rate. TNBC has substantial heterogeneity within the BC population. This study utilized our novel patient stratification and drug repositioning method to find subgroups of BC patients that share common genetic profiles and that may respond similarly to the recommended drugs. After further examination of the discovered patient subgroups, we identified five homogeneous druggable TNBC subgroups. A drug repositioning algorithm was then applied to find the drugs with a high potential for each subgroup. Most of the top drugs for these subgroups were chemotherapy used for various types of cancer, including BC. After analyzing the biological mechanisms targeted by these drugs, ferroptosis was the common cell death mechanism induced by the top drugs in the subgroups with neoplasm subdivision and race as clinical variables. In contrast, the antioxidative effect on cancer cells was the common targeted mechanism in the subgroup of patients with an age less than 50. Literature reviews were used to validate our findings, which could provide invaluable insights to streamline the drug repositioning process and could be further studied in a wet lab setting and in clinical trials.

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P-cadherin induces anoikis-resistance of matrix-detached breast cancer cells by promoting pentose phosphate pathway and decreasing oxidative stress

Cited by 31 publications

References 49 publications

Targeting Oxidative Phosphorylation-Proteasome Activity in Extracellular Detached Cells Promotes Anoikis and Inhibits Metastasis

Targeting Oxidative Phosphorylation-Proteasome Activity in Extracellular Detached Cells Promotes Anoikis and Inhibits Metastasis

A Bioinformatics-Based Analysis of an Anoikis-Related Gene Signature Predicts the Prognosis of Patients with Low-Grade Gliomas

Drug Repositioning and Subgroup Discovery for Precision Medicine Implementation in Triple Negative Breast Cancer

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