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Giant Lysosomes as a Chemotherapy Resistance Mechanism in Hepatocellular Carcinoma Cells.

ABSTRACT: Despite continuous improvements in therapeutic protocols, cancer-related mortality is still one of the main problems facing public health. The main cause of treatment failure is multi-drug resistance (MDR: simultaneous insensitivity to different anti-cancer agents), the underlying molecular and biological mechanisms of which include the activity of ATP binding cassette (ABC) proteins and drug compartmentalisation in cell organelles. We investigated the expression of the main ABC proteins and the role of cytoplasmic vacuoles in the MDR of six hepatocellular carcinoma (HCC) cell lines, and confirmed the accumulation of the yellow anti-cancer drug sunitinib in giant (four lines) and small cytoplasmic vacuoles of lysosomal origin (two lines). ABC expression analyses showed that the main ABC protein harboured by all of the cell lines was PGP, whose expression was not limited to the cell membrane but was also found on lysosomes. MTT assays showed that the cell lines with giant lysosomes were more resistant to sorafenib treatment than those with small lysosomes (p<0.01), and that verapamil incubation can revert this resistance, especially if it is administered after drug pre-incubation. The findings of this study demonstrate the involvement of PGP-positive lysosomes in drug sequestration and MDR in HCC cell lines. The possibility of modulating this mechanism using PGP inhibitors could lead to the development of new targeted strategies to enhance HCC treatment.

SUBMITTER: Colombo F

PROVIDER: S-EPMC4262459 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Downregulation of miR-33a-5p in Hepatocellular Carcinoma: A Possible Mechanism for Chemotherapy Resistance.

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NAP1L1 is a prognostic biomarker and contribute to doxorubicin chemotherapy resistance in human hepatocellular carcinoma.

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The Enhanced metastatic potential of hepatocellular carcinoma (HCC) cells with sorafenib resistance.

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| S-EPMC3823841 | biostudies-other

Melatonin Reduces Apoptosis Resistance of Hepatocellular Carcinoma Cells by Inhibiting BMAL1

Project description:Purpose: This study aimed to explore the role and molecular mechanism of brain and muscle ARNT-like protein 1 (BMAL1) in hepatocellular carcinoma (HCC), and the effect of melatonin on BMAL1 expression and apoptosis of HCC cells. Methods: We mainly used immunohistochemistry, western blot, cck-8 assays, flow cytometry, wound-healing assay, transwell assay, and RT-qPCR for this research. Results: The expression of BMAL1 protein was frequently up-regulated in the tissues and cell lines of HCC patients. Its high expression was significantly associated with tumor size, tumor differentiation degree, and shorter survival. In addition, cell functional experiments showed that BMAL1 could promote proliferation and migration, and inhibit apoptosis in HCC cell lines. Furthermore, the expression of BMAL1 was related to the endoplasmic reticulum stress (ERS) level. Knockdown of BMAL1 could inhibit the expression of ERS-related protein, while overexpression of BMAL1 led to the increase of ERS-related protein’s level. Low concentration of ERS led to the increase of BMAL1, and a certain degree of ERS in turn inhibited the expression of BMAL1. Melatonin promoted apoptosis of hepatoma cells by inhibiting the expression of BMAL1. Conclusion: BMAL1 plays a key role in HCC patients’ survival and tumor growth, which may be related to its interaction with ERS-related pathways. Melatonin can regulate ERS-related apoptosis resistance by inhibiting BMAL1 expression, promoting apoptosis of HCC cells.

| S-EPMC9178991 | biostudies-literature

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