Plumbagin induces paraptosis in cancer cells by disrupting the sulfhydryl homeostasis and proteasomal function

Binoy, Anupama; Nedungadi, Divya; Katiyar, Neeraj; Bose, Chinchu; Shankarappa, Sahadev A.; Nair, Bipin; Mishra, Nandita

doi:10.1016/j.cbi.2019.108733

Cited by 49 publications

(35 citation statements)

References 50 publications

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“…Therefore, rapamycin may be involved in the paraptosis process induced by HNK, thereby affecting the expression of LC3II/I and p62. These phenomena are common in paraptosis caused by other drugs including Manumycin A [28], and Plumbagin [41]. The processing of LC3 and the increase of p62 may be caused by the inhibition of proteasome activity.…”

Section: Discussionmentioning

confidence: 99%

Honokiol induces paraptosis-like cell death of acute promyelocytic leukemia via mTOR & MAPK signaling pathways activation

et al. 2021

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Acute promyelocytic leukemia (APL) is a blood system disease caused by the accumulation of a large number of immature blood cells in bone marrow. Although the introduction of all-trans retinoic acid (ATRA) and arsenic has reached a high level of complete remission rate and 5-year disease-free survival rate, the occurrence of various adverse reactions still severely affects the quality of life of patients. As a natural product, honokiol (HNK) has the advantages of low toxicity and high efficiency, and it is a potential drug for the treatment of cancer. Since cancer cells can escape apoptotic cell death through multiple adaptive mechanisms, HNK, a drug that induces cancer cell death in a nonapoptotic way, has attracted much interest. We found that HNK reduced the viability of human APL cell line (NB4 cells) by inducing paraptosis-like cell death. The process was accompanied by excessive reactive oxygen species (ROS), mitochondrial damage, endoplasmic reticulum stress, and increased microtubule-associated protein 1 light chain 3 (LC3) processing. The inactivation of proteasome activity was the main cause of misfolded and unfolded protein accumulation in endoplasmic reticulum, such as LC3II/I and p62. This phenomenon could be alleviated by adding cycloheximide (CHX), a protein synthesis inhibitor. We found that mTOR signaling pathway participated in paraptosis-like cell death induced by HNK in an autophagy-independent process. Moreover, the mitogen-activated protein kinase (MAPK) signaling pathway induced paraptosis of NB4 cells by promoting endoplasmic reticulum stress. In summary, these findings indicate that paraptosis may be a new way to treat APL, and provide novel insights into the potential mechanism of paraptosis-like cell death.

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Section: Discussionmentioning

confidence: 99%

Honokiol induces paraptosis-like cell death of acute promyelocytic leukemia via mTOR & MAPK signaling pathways activation

et al. 2021

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“…Researching new mechanisms of cancer cell death, such as paraptosis, is expected to help us solve this problem. Paraptosis has been confirmed to play an important role in cancer therapy (Binoy et al., 2019; Zhou et al., 2018).…”

Section: Discussionmentioning

confidence: 99%

Isorhamnetin induces the paraptotic cell death through ROS and the ERK/MAPK pathway in OSCC cells

Chen¹,

Song²,

Wang³

et al. 2020

Oral Diseases

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Objective There were rarely investigations on the effects and molecular mechanisms of oral squamous cell carcinoma (OSCC) cells when treated with isorhamnetin. This article assesses the anti‐cancer effect of isorhamnetin. Methods and materials Oral squamous cell carcinoma cells were treated with or without isorhamnetin. Cell proliferation, cell cycle arrest, cell migration, cell death, and the related signaling pathways were evaluated. Results The results revealed that cell proliferation was inhibited in a dose‐ and time‐dependent manner, which was confirmed by diminished cell viability and revealed by decreased in the number of cell colonies. In addition, the cell cycle arrested in the G2/M phase, and the protein levels of cyclin B1 and CDC2 were suppressed. Moreover, the cell migration was inhibited, and the protein levels of related proteins were modulated. Furthermore, it could be observed that abundant cytoplasmic vacuoles existed which that were derived from mitochondria and the endoplasmic reticulum. It was confirmed that cell death did not result from apoptosis and may have which may be apt to paraptosis. Isorhamnetin was observed to upregulate phosphorylated ERK cascades and increase intracellular reactive oxygen species levels. Conclusions Our study suggested that the anti‐cancer effect of isorhamnetin might trigger paraptosis, which may indicate a new therapeutic approach to OSCC.

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“…Earlier studies have mentioned that the α,β unsaturated structures which are present in chalcones are responsible for inhibiting the proteasome function in cancer cells (Bazzaro et al, 2011). Additionally, there are several piece of evidences which glorifies the accumulation of misfolded and unfolded proteins in the presence of α,β unsaturated compounds as the reason behind induction of paraptosis in cancer cells (Binoy et al, 2019; Kim et al, 2017; Seo et al, 2019). Similarly, in HRC treated cells we see that the polyubiquitinated proteins accumulate over time along with increasing levels of Bip and CHOP proteins, suggestive of ER stress and CHOP induced cell death.…”

Section: Discussionmentioning

confidence: 99%

“…60 μg of total protein lysates with 40 μM of fluorogenic peptide substrate, Suc‐Leu‐Leu‐Val‐Tyr‐AMC (Enzo Life Sciences) for proteasomal chymotrypsin‐like activity were incubated overnight at 37°C. The fluorescence reading was taken at 360/460 nm (Binoy et al, 2019).…”

Section: Methodsmentioning

confidence: 99%

“…Previous studies have shown that chalcones and their derivatives have potent anticancer, antimicrobial and anti-inflammatory activity (Katsori & Hadjipavlou-Litina, 2009;Nowakowska, 2007). Chalcone have been proven to be effective against hepatocellular carcinomas, glioblastomas, lung, bladder, colon and many other cancer types (Bittencourt et al, 2016;Chen et al, 2017;Kello et al, 2016;Ramirez-Tagle et al, 2016;Shen et al, 2007). Studies have revealed that chalcones when administered in the diet could reduce the tumor rates and thus provides support for further investigation of such natural derivatives for cancer prevention and therapy (Makita et al, 1996).…”

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confidence: 99%

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Proteasomal dysfunction and ER stress triggers 2′‐hydroxy‐retrochalcone‐induced paraptosis in cancer cells

Nedungadi

Binoy

Nanjan

et al. 2020

Cell Biology International

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Chalcones are biologically active class of compounds, known for their anticancer activities. Here we show for the first time that out of the six synthetic derivatives of chalcone tested, 2′‐hydroxy‐retrochalcone (HRC) was the most effective in inducing extensive cytoplasmic vacuolation mediated death called paraptosis in malignant breast and cervical cancer cells. The cell death by HRC is found to be nonapoptotic in nature due to the absence of DNA fragmentation, PARP cleavage, and phosphatidylserine externalization. It was also found to be nonautophagic as there was an increase in the levels of autophagic markers LC3I, LC3II and p62. Immunofluorescence with the endoplasmic reticulum (ER) marker protein calreticulin showed that the cytoplasmic vacuoles formed were derived from the ER. This ER dilation was due to ER stress as evidenced from the increase in polyubiquitinated proteins, Bip and CHOP. Docking studies revealed that HRC could bind to the Thr1 residue on the active site of the chymotrypsin‐like subunit of the proteasome. The inhibition of proteasomal activity was further confirmed by the fluorescence based assay of the chymotrypsin‐like subunit of the 26S proteasome. The cell death by HRC was also triggered by the collapse of mitochondrial membrane potential and depletion of ATP. Pretreatment with thiol antioxidants and cycloheximide were able to inhibit this programmed cell death. Thus our data suggest that HRC can effectively kill cancer cells via paraptosis, an alternative death pathway and can be a potential lead molecule for anticancer therapy.

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Plumbagin induces paraptosis in cancer cells by disrupting the sulfhydryl homeostasis and proteasomal function

Cited by 49 publications

References 50 publications

Honokiol induces paraptosis-like cell death of acute promyelocytic leukemia via mTOR & MAPK signaling pathways activation

Honokiol induces paraptosis-like cell death of acute promyelocytic leukemia via mTOR & MAPK signaling pathways activation

Isorhamnetin induces the paraptotic cell death through ROS and the ERK/MAPK pathway in OSCC cells

Proteasomal dysfunction and ER stress triggers 2′‐hydroxy‐retrochalcone‐induced paraptosis in cancer cells

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