Regulation of Autophagy by Protein Kinase C-ε in Breast Cancer Cells

Basu, Alakananda

doi:10.3390/ijms21124247

Cited by 17 publications

(19 citation statements)

References 38 publications

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“…The idea of a possible involvement of PKCε emerges from our recent findings, showing that this substrate contributes to the regulation of the negative crosstalk between EMT and autophagy orchestrated by FGFR2c during early steps of epidermal carcinogenesis [ 8 ]. Our hypothesis is also supported by a recent study, reporting that PKCε signaling can negatively impact on autophagy directly converging on MTOR in breast cancer cells [ 18 ].…”

Section: Introductionsupporting

confidence: 86%

Role of FGFR2c and Its PKCε Downstream Signaling in the Control of EMT and Autophagy in Pancreatic Ductal Adenocarcinoma Cells

Ranieri

Guttieri

Raffa

et al. 2021

Cancers

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Pancreatic ductal adenocarcinoma (PDAC) is a treatment-resistant malignancy characterized by a high malignant phenotype including acquired EMT signature and deregulated autophagy. Since we have previously described that the aberrant expression of the mesenchymal FGFR2c and the triggering of the downstream PKCε signaling are involved in epidermal carcinogenesis, the aim of this work has been to assess the contribution of these oncogenic events also in the pancreatic context. Biochemical, molecular and immunofluorescence approaches showed that FGFR2c expression impacts on PDAC cell responsiveness to FGF2 in terms of intracellular signaling activation, upregulation of EMT-related transcription factors and modulation of epithelial and mesenchymal markers compatible with the pathological EMT. Moreover, shut-off via specific protein depletion of PKCε signaling, activated by high expression of FGFR2c resulted in a reversion of EMT profile, as well as in a recovery of the autophagic process. The detailed biochemical analysis of the intracellular signaling indicated that PKCε, bypassing AKT and directly converging on ERK1/2, could be a signaling molecule downstream FGFR2c whose inhibition could be considered as possible effective therapeutic approach in counteracting aggressive phenotype in cancer.

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Section: Introductionsupporting

confidence: 86%

Role of FGFR2c and Its PKCε Downstream Signaling in the Control of EMT and Autophagy in Pancreatic Ductal Adenocarcinoma Cells

Ranieri

Guttieri

Raffa

et al. 2021

Cancers

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“…The two TNBC cell lines (MDA-MB-468 and BT549) were placed in a six-well plate according to their growth conditions, and the growth density was 80–90% on the second day. The complete medium was replaced with calcium- and phosphorus-free EBSS, and the cells were collected for protein extraction after being treated for different time-points (0, 2 and 4 h) ( 21 ).…”

Section: Methodsmentioning

confidence: 99%

HORMAD1 promotes docetaxel resistance in triple negative breast cancer by enhancing DNA damage tolerance

et al. 2021

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HORMA domain-containing protein 1 (HORMAD1), is normally expressed only in the germline, but is frequently re-activated in human triple-negative breast cancer (TNBC); however, its function in TNBC is largely unknown. In the present study, the expression and biological significance of HORMAD1 in human TNBC was evaluated. Bioinformatics analysis and reverse transcription-quantitative PCR were used to evaluate HORMAD1 expression in datasets and cell lines. HORMAD1 protein expression was detected in TNBC samples using immunohistochemical assays, and the effect of HORMAD1 on cell proliferation was determined using Cell Counting Kit-8, plate colony formation and standard growth curve assays. Cell cycle, reactive oxygen species (ROS) and apoptosis analyses were conducted using flow cytometry. The activity of caspases was measured using caspase activity assay kit. The levels of key apoptosis regulators and autophagy markers were detected by western blot analysis. TNBC cell survival and apoptosis were not influenced by small interfering RNA targeting HORMAD1 alone; however, HORMAD1 knockdown enhanced autophagy and docetaxel (Doc)-induced apoptosis, compared with the control group. Furthermore, higher ROS levels and caspase-3, -8 and -9 activity were detected in MDA-MB-436 TNBC cells with HORMAD1 knockdown upon exposure to Doc. The levels of the induced DNA damage marker γH2AX were also higher, while those of the DNA repair protein RAD51 were lower in TNBC cells with HORMAD1 knockdown compared with the controls. Furthermore, the expression of the autophagy marker P62 was enhanced in MDA-MB-231 cells in response to HORMAD1 overexpression. Notably, Doc-induced apoptosis was similarly increased by both HORMAD1 overexpression and treatment with the autophagy inhibitor, 3-methyladenine (3MA); however, the Doc-induced increase in autophagy was not inhibited by 3MA. The present data indicated that HORMAD1 was involved in autophagy and that the inhibition of autophagy can partially enhance the induction of apoptosis by Doc. The role of HORMAD1 in the DNA damage tolerance of tumor cells may be the main reason for Doc resistance; hence, HORMAD1 could be an important therapeutic target in TNBC.

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“…However, although miconazole induced LC3-II expression, ATG5 expression was unaffected. Other studies have also observed no change in the protein expression level of ATG5 in experimentally induced autophagy (27,28). In addition, the activity of ATG5 is reportedly regulated by phosphorylation (29).…”

Section: Discussionmentioning

confidence: 90%

Miconazole induces autophagic death in glioblastoma cells via reactive oxygen species‑mediated endoplasmic reticulum stress

et al. 2021

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Miconazole is an antifungal agent that is used for the treatment of superficial mycosis. However, recent studies have indicated that miconazole also exhibits potent anticancer effects in various types of cancer via the activation of apoptosis. The main aim of the present study was to observe the effect of miconazole on autophagic cell death of cancer cells. Cytotoxicity was measured by viable cell counting after miconazole treatment in glioblastoma cell lines (U343MG, U87MG and U251MG). Induction of autophagy was analyzed by examining microtubule-associated protein light chain 3 (LC3)-II expression levels using western blotting and by detecting GFP-LC3 translocation using a fluorescence microscope. Intracellular ROS production was measured using a fluorescent probe, 2′,7′-dichlorodihydrofluorescein diacetate. It was found that miconazole induced autophagic cell death in the U251MG glioblastoma cell line via the generation of reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress response. An association between miconazole-induced ROS production and autophagy was also identified; in particular, pretreatment of the cells with a ROS scavenger resulted in a reduction in the levels of LC3-II. Miconazole-induced ER stress was associated with increases in binding immunoglobulin protein (BiP), inositol-requiring enzyme 1α (IRE1α) and CHOP expression, and phospho-eIF2α levels. The inhibition of ER stress via treatment with 4-phenylbutyric acid or BiP knockdown reduced miconazole-induced autophagy and cell death. These findings suggest that miconazole induces autophagic cell death by inducing an ROS-dependent ER stress response in U251MG glioma cancer cells and provide new insights into the potential antiproliferative effects of miconazole.

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Regulation of Autophagy by Protein Kinase C-ε in Breast Cancer Cells

Cited by 17 publications

References 38 publications

Role of FGFR2c and Its PKCε Downstream Signaling in the Control of EMT and Autophagy in Pancreatic Ductal Adenocarcinoma Cells

Role of FGFR2c and Its PKCε Downstream Signaling in the Control of EMT and Autophagy in Pancreatic Ductal Adenocarcinoma Cells

HORMAD1 promotes docetaxel resistance in triple negative breast cancer by enhancing DNA damage tolerance

Miconazole induces autophagic death in glioblastoma cells via reactive oxygen species‑mediated endoplasmic reticulum stress

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