Pentoxifylline triggers autophagy via ER stress response that interferes with Pentoxifylline induced apoptosis in human melanoma cells

Sharma, K. K.; Ishaq, Mohammad; Sharma, Gaurav; Khan, Mohammad Aslam; Dutta, Rajesh Kumar; Majumdar, S.

doi:10.1016/j.bcp.2015.12.018

Cited by 16 publications

(15 citation statements)

References 45 publications

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“…It encapsulates α‐Syn into double‐membraned vesicles to form a phagophore, known as autophagosomes . The ER stress and autophagy are generally assumed as independent of each other and severing distinct functions; however, increasingly evidences have indicated that ER stress triggers autophagy, which disposes of unfolded proteins in cells . ER stress is involved in regulation of a series of cell processes, including autophagy, apoptosis and the complicated regulatory network of them.…”

Section: Introductionmentioning

confidence: 99%

Effect of the cross‐talk between autophagy and endoplasmic reticulum stress on Mn‐induced alpha‐synuclein oligomerization

Liu

Yan

Tan

et al. 2017

Environmental Toxicology

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Overexposure to manganese (Mn) has been known to induce alpha-synuclein (α-Syn) oligomerization, which is degraded mainly depending on endoplasmic reticulum stress (ER stress) and autophagy pathways. However, little data reported the cross-talk between ER stress and autophagy on Mn-induced α-Syn oligomerization. To explore the relationship between ER stress and autophagy, we used 4-phenylbutyric acid (4-PBA, the ER stress inhibitor), rapamycin (Rap, autophagy activator) and 3-methyladenine (3-MA, autophagy inhibitor) in mice model of manganism. After 4 weeks of treatment with Mn, both ER stress and autophagy were activated. Exposed to Mn also resulted in α-Syn oligomerization and neuronal cell damage in the brain tissue of mice, which could be relieved by 4-PBA pretreatment. Moreover, when the ER stress was inhibited, the activation of autophagy was also inhibited. Rap pretreatment significantly activated autophagy and decreased α-Syn oligomers. However, 3-MA pretreatment inhibited autophagy resulting in increase of α-Syn oligomers, and compensatorily activated PERK signaling pathway. Our results also demonstrated that the inhibition of autophagy by 3-MA aggravated neuronal cell damage. The findings clearly demonstrated that the cross-talking between autophagy and ER stress might play an important role in the α-Syn oligomerization and neurotoxicity by Mn.

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Section: Introductionmentioning

confidence: 99%

Effect of the cross‐talk between autophagy and endoplasmic reticulum stress on Mn‐induced alpha‐synuclein oligomerization

Liu

Yan

Tan

et al. 2017

Environmental Toxicology

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“…This result is in agreement with several studies showing a tight relationship between autophagy and ER stress. 34,35 CPE that lacks its N-terminal domain harbors an opposite activity in controlling the Wnt cascade. 6 Furthermore, the N-terminal portion is capable of inhibiting the Wnt pathway by decreasing the amounts of β-catenin and Wnt3a, even when reduced to the N'-terminal 20 residues peptide.…”

Section: Discussionmentioning

confidence: 99%

Carboxypeptidase E (CPE) inhibits the secretion and activity of Wnt3a

et al. 2016

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The Wnt pathway has essential roles in cell proliferation, cell fate determination and tumorigenesis by regulating the expression of a wide range of target genes. As a core signaling cascade, the canonical Wnt pathway is regulated at different levels by numerous proteins. We have previously shown that carboxypeptidase E (CPE) is a novel regulator of the canonical Wnt signaling pathway. Here, we show that CPE and the Wnt3a ligand are co-secreted from cells. We show that although the C'-terminal Lys residue of Wnt3a is critical for its activity and is important for the effect of CPE on the Wnt pathway, CPE does not execute its effect by removing this Wnt3a residue. Interestingly, CPE through its N'-terminal sequence, forms aggregates with Wnt3a and possible endoplasmic reticulum (ER) stress leading to its loss of function. Together, our current results provide a mechanistic insight into the way CPE regulates the canonical Wnt signaling pathway.

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“…To date, the role of ERK in the induction of apoptosis is still under debate (34). ERK inhibition has been reported to be necessary for apoptosis in mda-mB-231 and other tumor cells (17,32,(35)(36)(37)(38). However, others have shown that ERK activation is required for the induction of apoptosis (39)(40)(41)(42)(43).…”

Section: Discussionmentioning

confidence: 99%

Synergistic promoting effects of pentoxifylline and simvastatin on the apoptosis of triple-negative MDA-MB-231 breast cancer cells

Castellanos-Esparza

Huang

et al. 2018

Int J Oncol

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Pentoxifylline (PTX), a xanthine family molecule and simvastatin (SIM), an anti-hypercholesterolemic agent, have recently been considered as sensitizers to chemotherapy and radiotherapy. The present in vitro study evaluated their antitumor synergistic effects on MDA‑MB‑231 breast cancer cells characterized by the triple‑negative phenotype (TNP). The anti-proliferative effects of these two agents were evaluated by MTT and clonogenic assays. Cell cycle progression was examined using propidium iodide staining. Apoptosis was investigated by Annexin V labeling, and by examining caspase 3 activity and DNA fragmentation. Autophagic vesicles and reactive oxygen species (ROS) levels were monitored by flow cytometry. Western blot analysis was performed to evaluate molecular targets. Our results revealed that when used alone, PTX and SIM exerted antitumor effects. Nevertheless, used in combination, the inhibition of cell proliferation was synergistically superior (80% vs 42%) than that observed following treatment with each agent alone after 48 h. PTX alone (0.5 mM) induced both apoptosis (25%) and autophagy (25%); however, when used in combination with SIM (0.5 µM), the balance between these processes was disrupted and the cells underwent apoptosis (>65%) as opposed to autophagy (<13%). This imbalance was associated with an increase in ERK1/2 and AKT activation, but not with an increase in mTOR phosphorylation, and with the suppression of the NF-κB pathway. In addition, in the cells treated with both agents, almost 78% of the cells were arrested at the G0/G1 phase and lost their colony-forming ability (38±5%) compared to the cells treated with PTX alone (115±5%). On the whole, these results suggest that the induction of autophagy may be a protective mechanism preventing MDA‑MB‑231 cancer cell death. The combined use of PTX and SIM may drive dormant autophagic cancer cells to undergo apoptosis and thus this may be a novel treatment strategy for breast cancer characterized by the TNP.

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Pentoxifylline triggers autophagy via ER stress response that interferes with Pentoxifylline induced apoptosis in human melanoma cells

Cited by 16 publications

References 45 publications

Effect of the cross‐talk between autophagy and endoplasmic reticulum stress on Mn‐induced alpha‐synuclein oligomerization

Effect of the cross‐talk between autophagy and endoplasmic reticulum stress on Mn‐induced alpha‐synuclein oligomerization

Carboxypeptidase E (CPE) inhibits the secretion and activity of Wnt3a

Synergistic promoting effects of pentoxifylline and simvastatin on the apoptosis of triple-negative MDA-MB-231 breast cancer cells

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