Common Metabolic Pathways Implicated in Resistance to Chemotherapy Point to a Key Mitochondrial Role in Breast Cancer*

Abad, Etna; García-Mayea, Yoelsis; Mir, Cristina; Sebastián, David; Zorzano, António; Potěšil, David; Zdráhal, Zbyněk; Lyakhovich, Alex; Lleonart, Matilde E.

doi:10.1074/mcp.ra118.001102

Cited by 34 publications

(25 citation statements)

References 37 publications

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“…Furthermore, the use of antidiabetic drugs including metformin and GLP1 mimetics showed promising results in animal models of AD (Jha et al, 2017;Holscher, 2018). Moreover, considering that insulin signaling activation regulates mitochondrial functions (Butterfield et al, 2014a;Abad et al, 2019;Wardelmann et al, 2019) and that mitochondria are dysfunctional in DS (Mollo et al, 2020), it is conceivable to think rescuing insulin signaling activation in DS would be beneficial also with respect to mitochondrial performances. Metformin, a well-known drugs used to treat insulin resistance, was effective in recovering mitochondrial structure and functions in trisomic cells (Izzo et al, 2018).…”

Section: Resultsmentioning

confidence: 99%

Down Syndrome Is a Metabolic Disease: Altered Insulin Signaling Mediates Peripheral and Brain Dysfunctions

et al. 2020

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Down syndrome (DS) is the most frequent chromosomal abnormality that causes intellectual disability, resulting from the presence of an extra complete or segment of chromosome 21 (HSA21). In addition, trisomy of HSA21 contributes to altered energy metabolism that appears to be a strong determinant in the development of pathological phenotypes associated with DS. Alterations include, among others, mitochondrial defects, increased oxidative stress levels, impaired glucose, and lipid metabolism, finally resulting in reduced energy production and cellular dysfunctions. These molecular defects seem to account for a high incidence of metabolic disorders, i.e., diabetes and/or obesity, as well as a higher risk of developing Alzheimer's disease (AD) in DS. A dysregulation of the insulin signaling with reduced downstream pathways represents a common pathophysiological aspect in the development of both peripheral and central alterations leading to diabetes/obesity and AD. This is further strengthened by evidence showing that the molecular mechanisms responsible for such alterations appear to be similar between peripheral organs and brain. Considering that DS subjects are at high risk to develop either peripheral or brain metabolic defects, this review will discuss current knowledge about the link between trisomy of HSA21 and defects of insulin and insulin-related pathways in DS. Drawing the molecular signature underlying these processes in DS is a key challenge to identify novel drug targets and set up new prevention strategies aimed to reduce the impact of metabolic disorders and cognitive decline.

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Section: Resultsmentioning

confidence: 99%

Down Syndrome Is a Metabolic Disease: Altered Insulin Signaling Mediates Peripheral and Brain Dysfunctions

et al. 2020

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“…In metabolomic and proteomic studies, our group has recently demonstrated common regulatory pathways to distinguish resistant cancer cells (non-CSCs) and CSCs from parental cells using a breast cancer model [13]. Hence, it is of major relevance to focus on those proteins present in resistant cancer cells and CSCs in order to design more effective treatment strategies that might synergistically act with standard chemotherapy [14].…”

Section: Introductionmentioning

confidence: 99%

TSPAN1: A Novel Protein Involved in Head and Neck Squamous Cell Carcinoma Chemoresistance

García-Mayea

Mir

Carballo

et al. 2020

Cancers

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Sensitization of resistant cells and cancer stem cells (CSCs) represents a major challenge in cancer therapy. A proteomic study revealed tetraspanin-1 (TSPAN1) as a protein involved in acquisition of cisplatin (CDDP) resistance (Data are available via ProteomeXchange with identifier PXD020159). TSPAN1 was found to increase in CDDP-resistant cells, CSCs and biopsies from head and neck squamous cell carcinoma (HNSCC) patients. TSPAN1 depletion in parental and CDDP-resistant HNSCC cells reduced cell proliferation, induced apoptosis, decreased autophagy, sensitized to chemotherapeutic agents and inhibited several signaling cascades, with phospho-SRC inhibition being a major common target. Moreover, TSPAN1 depletion in vivo decreased the size and proliferation of parental and CDDP-resistant tumors and reduced metastatic spreading. Notably, CDDP-resistant tumors showed epithelial–mesenchymal transition (EMT) features that disappeared upon TSPAN1 inhibition, suggesting a link of TSPAN1 with EMT and metastasis. Immunohistochemical analysis of HNSCC specimens further revealed that TSPAN1 expression was correlated with phospho-SRC (pSRC), and inversely with E-cadherin, thus reinforcing TSPAN1 association with EMT. Overall, TSPAN1 emerges as a novel oncogenic protein and a promising target for HNSCC therapy.

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“…Concerning breast cancer, it is one of the most commonly diagnosed cancers worldwide, generally known as metastatic cancer resistant to chemotherapy (19,20). Therefore, many investigations are focused on finding new drugs and drug delivery systems to fight it.…”

Section: Introductionmentioning

confidence: 99%

pH-responsive polymer micelles for methotrexate delivery at tumor microenvironments

et al. 2020

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Methotrexate (MTX) anticancer drug was successfully loaded and released in a controlled manner from polymer micelles made of a diblock copolymer of poly(monomethoxy ethylene glycol)-b-poly(ε-caprolactone) (mPEG-PCL). The empty and MTX-loaded micelles (MTX/mPEG-PCL) were characterized by electron microscopy. The drug release dependence upon pH 5.4, 6.5, and 7.4 for 30 days was proven and characterized by UV-Vis spectroscopy. The cytotoxic effect of MTX/mPEG-PCL micelles on MCF-7 breast cancer cells was evaluated through an MTT assay. The morphological analysis indicated the successful formation of micelles of 76 and 131 nm for empty and MTX-loaded micelles, respectively. An encapsulation efficiency of 70.2% and a loading capacity of 8.8% were obtained. The in vitro release of MTX showed a gradual and sustained profile over 22 days, with a clear trend to much higher release at acidic pH (80 and 90% for pH 6.7 and 5.5, respectively). The MTX/mPEG-PCL micelles showed an IC50 of MCF-7 cells at 30 µg mL−1. The results suggested that MTX/mPEG-PCL could be a promising drug delivery system for cancer treatment.

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Common Metabolic Pathways Implicated in Resistance to Chemotherapy Point to a Key Mitochondrial Role in Breast Cancer*

Cited by 34 publications

References 37 publications

Down Syndrome Is a Metabolic Disease: Altered Insulin Signaling Mediates Peripheral and Brain Dysfunctions

Down Syndrome Is a Metabolic Disease: Altered Insulin Signaling Mediates Peripheral and Brain Dysfunctions

TSPAN1: A Novel Protein Involved in Head and Neck Squamous Cell Carcinoma Chemoresistance

pH-responsive polymer micelles for methotrexate delivery at tumor microenvironments

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