Influence of lysosomal sequestration on multidrug resistance in cancer cells

Halaby, Reginald

doi:10.20517/cdr.2018.23

Cited by 25 publications

(28 citation statements)

References 104 publications

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“…Lastly, one of the highlights of our current study is identification of the effect of GH action in melanoma in promoting MITF-mediated melanogenesis in melanosomes. In malignant melanoma, drug sequestration in melanosomes has been reported to contribute to chemoresistance to cisplatin [26], similar to the effects of vesicular drug sequestration conferring cancer drug resistance [24,72]. ABC-transporters, which we and others have previously described as targets of GH–GHR action in melanoma [21] and breast cancer [22], are also implicated in active sequestration of drugs in melanosomes [28].…”

Section: Discussionmentioning

confidence: 99%

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Growth Hormone Upregulates Melanocyte-Inducing Transcription Factor Expression and Activity via JAK2-STAT5 and SRC Signaling in GH Receptor-Positive Human Melanoma

Basu

Kulkarni

Qian

et al. 2019

Cancers

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Growth hormone (GH) facilitates therapy resistance in the cancers of breast, colon, endometrium, and melanoma. The GH-stimulated pathways responsible for this resistance were identified as suppression of apoptosis, induction of epithelial-to-mesenchymal transition (EMT), and upregulated drug efflux by increased expression of ATP-binding cassette containing multidrug efflux pumps (ABC-transporters). In extremely drug-resistant melanoma, ABC-transporters have also been reported to mediate drug sequestration in intracellular melanosomes, thereby reducing drug efficacy. Melanocyte-inducing transcription factor (MITF) is the master regulator of melanocyte and melanoma cell fate as well as the melanosomal machinery. MITF targets such as the oncogene MET, as well as MITF-mediated processes such as resistance to radiation therapy, are both known to be upregulated by GH. Therefore, we chose to query the direct effects of GH on MITF expression and activity towards conferring chemoresistance in melanoma. Here, we demonstrate that GH significantly upregulates MITF as well as the MITF target genes following treatment with multiple anticancer drug treatments such as chemotherapy, BRAF-inhibitors, as well as tyrosine-kinase inhibitors. GH action also upregulated MITF-regulated processes such as melanogenesis and tyrosinase activity. Significant elevation in MITF and MITF target gene expression was also observed in mouse B16F10 melanoma cells and xenografts in bovine GH transgenic (bGH) mice compared to wild-type littermates. Through pathway inhibitor analysis we identified that both the JAK2-STAT5 and SRC activities were critical for the observed effects. Additionally, a retrospective analysis of gene expression data from GTEx, NCI60, CCLE, and TCGA databases corroborated our observed correlation of MITF function and GH action. Therefore, we present in vitro, in vivo, and in silico evidence which strongly implicates the GH–GHR axis in inducing chemoresistance in human melanoma by driving MITF-regulated and ABC-transporter-mediated drug clearance pathways.

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Section: Discussionmentioning

confidence: 99%

“…Drug sequestration in intracellular compartments such as lysosomes and endosomes dampens the cytotoxic effects of anticancer drugs [24,25]. Melanoma tumors are uniquely enabled to sequester anticancer compounds into intracellular vesicles called melanosomes, which is also the site of melanin synthesis.…”

Section: Introductionmentioning

confidence: 99%

Growth Hormone Upregulates Melanocyte-Inducing Transcription Factor Expression and Activity via JAK2-STAT5 and SRC Signaling in GH Receptor-Positive Human Melanoma

Basu

Kulkarni

Qian

et al. 2019

Cancers

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“…It would be interesting, in future work, to couple this model with a mathematical model of the circadian clock [79] and introduce circadian regulation into the system. In addition, given the important role of lysosomes [80,81,82] and the circadian clock [83,84,85,86] in cancer, it would be relevant to further investigate the possible interplay between the circadian clock and lysosomes in a cancer context.…”

Section: Discussionmentioning

confidence: 99%

A Mathematical Model of Lysosomal Ion Homeostasis Points to Differential Effects of Cl− Transport in Ca2+ Dynamics

Astaburuaga

Haro

Stauber

et al. 2019

Cells

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The establishment and maintenance of ion gradients between the interior of lysosomes and the cytosol are crucial for numerous cellular and organismal functions. Numerous ion transport proteins ensure the required variation in luminal concentrations of the different ions along the endocytic pathway to fit the needs of the organelles. Failures in keeping proper ion homeostasis have pathological consequences. Accordingly, several human diseases are caused by the dysfunction of ion transporters. These include osteopetrosis, caused by the dysfunction of Cl−/H+ exchange by the lysosomal transporter ClC-7. To better understand how chloride transport affects lysosomal ion homeostasis and how its disruption impinges on lysosomal function, we developed a mathematical model of lysosomal ion homeostasis including Ca2+ dynamics. The model recapitulates known biophysical properties of ClC-7 and enables the investigation of its differential activation kinetics on lysosomal ion homeostasis. We show that normal functioning of ClC-7 supports the acidification process, is associated with increased luminal concentrations of sodium, potassium, and chloride, and leads to a higher Ca2+ uptake and release. Our model highlights the role of ClC-7 in lysosomal acidification and shows the existence of differential Ca2+ dynamics upon perturbations of Cl−/H+ exchange and its activation kinetics, with possible pathological consequences.

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“…Briefly, drugs can be sequestrated in lysosomes through passive diffusion or active transportation, which prevents drugs from reaching their intracellular targets [220]. For passive diffusion, lysosomes are distinguished by their luminal pH of about 4.5-5, hence lysosomes are able to sequester lipophilic, weakly basic drugs without the help of transporters [221,222]. Once accumulate in lysosomes, these drugs can hardly pass the lysosomal membrane because of protonation [220].…”

Section: Regulation Of Tumor Cell Chemoresistance By Lysosomesmentioning

confidence: 99%

“…Once accumulate in lysosomes, these drugs can hardly pass the lysosomal membrane because of protonation [220]. Alternatively, chemotherapy drugs can also enter lysosomes through trafficking by P-glycoprotein (P-gp), an ATP-dependent efflux pump [221]. Normally, P-gp is embedded in the plasma membrane, but it can be incorporated into lysosomal membranes through intracellular trafficking [223].…”

Section: Regulation Of Tumor Cell Chemoresistance By Lysosomesmentioning

confidence: 99%

Role of lysosomes in physiological activities, diseases, and therapy

Zhang¹,

Yue

et al. 2021

J Hematol Oncol

176

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Long known as digestive organelles, lysosomes have now emerged as multifaceted centers responsible for degradation, nutrient sensing, and immunity. Growing evidence also implicates role of lysosome-related mechanisms in pathologic process. In this review, we discuss physiological function of lysosomes and, more importantly, how the homeostasis of lysosomes is disrupted in several diseases, including atherosclerosis, neurodegenerative diseases, autoimmune disorders, pancreatitis, lysosomal storage disorders, and malignant tumors. In atherosclerosis and Gaucher disease, dysfunction of lysosomes changes cytokine secretion from macrophages, partially through inflammasome activation. In neurodegenerative diseases, defect autophagy facilitates accumulation of toxic protein and dysfunctional organelles leading to neuron death. Lysosomal dysfunction has been demonstrated in pathology of pancreatitis. Abnormal autophagy activation or inhibition has been revealed in autoimmune disorders. In tumor microenvironment, malignant phenotypes, including tumorigenesis, growth regulation, invasion, drug resistance, and radiotherapy resistance, of tumor cells and behaviors of tumor-associated macrophages, fibroblasts, dendritic cells, and T cells are also mediated by lysosomes. Based on these findings, a series of therapeutic methods targeting lysosomal proteins and processes have been developed from bench to bedside. In a word, present researches corroborate lysosomes to be pivotal organelles for understanding pathology of atherosclerosis, neurodegenerative diseases, autoimmune disorders, pancreatitis, and lysosomal storage disorders, and malignant tumors and developing novel therapeutic strategies.

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Influence of lysosomal sequestration on multidrug resistance in cancer cells

Cited by 25 publications

References 104 publications

Growth Hormone Upregulates Melanocyte-Inducing Transcription Factor Expression and Activity via JAK2-STAT5 and SRC Signaling in GH Receptor-Positive Human Melanoma

Growth Hormone Upregulates Melanocyte-Inducing Transcription Factor Expression and Activity via JAK2-STAT5 and SRC Signaling in GH Receptor-Positive Human Melanoma

A Mathematical Model of Lysosomal Ion Homeostasis Points to Differential Effects of Cl− Transport in Ca2+ Dynamics

Role of lysosomes in physiological activities, diseases, and therapy

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