Energy deprivation by silibinin in colorectal cancer cells

Raina, Komal; Agarwal, Chapla; Wadhwa, Ritambhara; Serkova, Natalie J.; Agarwal, Rajesh

doi:10.4161/auto.23960

Cited by 71 publications

(33 citation statements)

References 54 publications

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“…For example, growth factor signaling [(such as insulin-like growth factor (IGF-1) induced signals)] governed by the receptor tyrosine kinases and mediated via the PI3K/Akt and the MAPK pathway is often deregulated and constitutively activated in cancer cells [35-37]. In CRC, IGF-1 is a potent mitogen that regulates proliferation and survival of CRC cells via both Akt- and MAPK- mediated signaling [26, 36, 37], which suggests that agents are needed to also impair such signaling to achieve better success in overcoming apoptosis resistance in CRC cells. Accordingly, we also performed additional studies to assess whether, in addition to targeting ER stress and associated pathways, GSE also inhibits survival and mitogenic signaling in human CRC cells.…”

Section: Resultsmentioning

confidence: 99%

“…Cells were maintained at 37°C in a humidified 5% CO 2 atmosphere in DMEM (HCT116) and RMPI (SW480 and SW620) media supplemented with 10% FBS and 1% penicillin/streptomycin. For serum starvation experiments, at 60% confluency, cells were serum starved (SS) for 24 h, treated with different concentrations of GSE and after 6h, stimulated with IGF-1 (50 ng/mL) for 15 min, and harvested as described previously [26]. …”

Section: Methodsmentioning

confidence: 99%

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Target Identification of Grape Seed Extract in Colorectal Cancer Using Drug Affinity Responsive Target Stability (DARTS) Technique: Role of Endoplasmic Reticulum Stress Response Proteins

Derry¹,

Somasagara²,

Raina³

et al. 2014

CCDT

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Various natural agents, including grape seed extract (GSE), have shown considerable chemopreventive and anti-cancer efficacy against different cancers in pre-clinical studies; however, their specific protein targets are largely unknown and thus, their clinical usefulness is marred by limited scientific evidences about their direct cellular targets. Accordingly, herein, employing, for the first time, the recently developed drug affinity responsive target stability (DARTS) technique, we aimed to profile the potential protein targets of GSE in human colorectal cancer (CRC) cells. Unlike other methods, which can cause chemical alteration of the drug components to allow for detection, this approach relies on the fact that a drug bound protein may become less susceptible to proteolysis and hence the enriched proteins can be detected by Mass Spectroscopy methods. Our results, utilizing the DARTS technique followed by examination of the spectral output by LC/MS and the MASCOT data, revealed that GSE targets endoplasmic reticulum (ER) stress response proteins resulting in overall down regulation of proteins involved in translation and that GSE also causes oxidative protein modifications, specifically on methionine amino acids residues on its protein targets. Corroborating these findings, mechanistic studies revealed that GSE indeed caused ER stress and strongly inhibited PI3k-Akt–mTOR pathway for its biological effects in CRC cells. Furthermore, bioenergetics studies indicated that GSE also interferes with glycolysis and mitochondrial metabolism in CRC cells. Together, the present study identifying GSE molecular targets in CRC cells, combined with its efficacy in vast pre-clinical CRC models, further supports its usefulness for CRC prevention and treatment.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Target Identification of Grape Seed Extract in Colorectal Cancer Using Drug Affinity Responsive Target Stability (DARTS) Technique: Role of Endoplasmic Reticulum Stress Response Proteins

Derry¹,

Somasagara²,

Raina³

et al. 2014

CCDT

Self Cite

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“…However, emerging evidence indicated that the self‐cannibalistic function may be associated with excessive cell death under certain conditions31, 32 Therefore, more and more scholars described the role of autophagy in various pathophysiological processes as a double‐edged sword 33, 34, 35, 36. From the previous study, the autophagy was proved to be a protective role for AKI37, 38 .…”

Section: Discussionmentioning

confidence: 99%

TAK1 mediates excessive autophagy via p38 and ERK in cisplatin‐induced acute kidney injury

Zhou

Fan

Zhong

et al. 2018

J Cellular Molecular Medi

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The ability of cisplatin (cis‐diamminedichloroplatinum II) toxicity to induce acute kidney injury (AKI) has attracted people's attention and concern for a long time, but its molecular mechanisms are still widely unknown. We found that the expression of transforming growth factor‐β (TGF‐β)‐activated kinase 1 (TAK1) could be increased in kidneys of mice administrated with cisplatin. Autophagy is an evolutionarily conserved catabolic pathway and is involved in various acute and chronic injuries. Moreover, p38 MAPK (mitogen‐activated protein kinase) and ERK regulate autophagy in response to various stimuli. Therefore, our hypothesis is that cisplatin activates TAK1, which phosphorylates p38 and ERK, leading to excessive autophagy of tubular epithelial cells and thus exacerbating kidney damage. Here, BALB/c mice were intraperitoneally injected with a TAK1 inhibitor and were then administrated with sham or cisplatin at 20 mg/kg by intraperitoneal injection. Compared with mice in the vehicle cisplatin group, mice intraperitoneally injected with a TAK1 inhibitor were found to have lower serum creatinine and less tubular damage following cisplatin‐induced AKI. Furthermore, inhibition of TAK1 reduced p38 and Erk phosphorylation, decreased expression of LC3II and reversed the down‐regulation of P62 expression induced by cisplatin. The hypothesis was verified with tubular epithelial cells administrated with cisplatin in vitro. Finally, p38 inhibitor or ERK inhibitor abated autophagy activation and cell viability reduction in tubular epithelial cells treated with cisplatin plus TAK1 overexpression vector. Taken together, our results show that cisplatin activates TAK1, which phosphorylates p38 and ERK, leading to excessive autophagy of tubular epithelial cells that exacerbates kidney damage.

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“…Metabolomics analysis has been increasingly used to reveal the underlying mechanisms of action for evidence-based Chinese medicine including Chinese medicine syndromes “Zheng”, action of Chinese medicine, preventive treatment, Chinese medical formulae, and acupuncture efficacy [15]. This methodology also has the potential for disease diagnosis, screening of new drugs, evaluation of the therapeutic efficacy, safety monitoring, and discovery of new biomarkers of therapeutics or TCM products [16, 17]. For example, Raina et al [17] reported a metabolomics study utilizing quantitative high-resolution nuclear magnetic resonance spectroscopy ( 1 H-, 13 C- and 31 P-NMR) to profile the metabolism and energy state of silibinin-treated colorectal cancer (CRC) cells in complementing accompanying proteomics analysis and associated apoptosis in response to silibinin-induced energy restriction.…”

Section: Introductionmentioning

confidence: 99%

“…This methodology also has the potential for disease diagnosis, screening of new drugs, evaluation of the therapeutic efficacy, safety monitoring, and discovery of new biomarkers of therapeutics or TCM products [16, 17]. For example, Raina et al [17] reported a metabolomics study utilizing quantitative high-resolution nuclear magnetic resonance spectroscopy ( 1 H-, 13 C- and 31 P-NMR) to profile the metabolism and energy state of silibinin-treated colorectal cancer (CRC) cells in complementing accompanying proteomics analysis and associated apoptosis in response to silibinin-induced energy restriction. Their results suggest that silibinin may dually induce apoptosis and autophagy by restricting glucose uptake and energy production to inhibit CRC cells.…”

Section: Introductionmentioning

confidence: 99%

Macranthoidin B Modulates Key Metabolic Pathways to Enhance ROS Generation and Induce Cytotoxicity and Apoptosis in Colorectal Cancer

Fan

Rao

Zhang³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Induction of oxidative stress and reactive oxygen species (ROS) mediated-apoptosis have been utilized as effective strategies in anticancer therapy. Macranthoidin B (MB) is a potent inducer of ROS-mediated apoptosis in cancer, but its mechanism of action is poorly understood. Method: Superoxide production with MB exposure in colorectal cancer (CRC) cells was measured using lucigenin chemiluminescence and real-time PCR. MB’s inhibitory effect on proliferation and viability of CRC cells was determined by proliferation assays. MB’s effect on apoptosis of CRC cells was determined by Western blotting and annexin V-FITC/PI staining. MB’s effect on the growth of CRC xenografts in mice was assessed. An established metabolomics profiling platform combining ultra-performance liquid chromatography-tandem mass spectrometry (LC-MS) with gas chromatography-mass spectrometry (GC-MS) was performed to determine MB’s effect on total metabolite variation in CRC cells. Results: We found that MB increases ROS generation via modulating key metabolic pathways. Using metabolomics profiling platform combining LC-MS with GC-MS, a total of 236 metabolites were identified in HCT-116 cells in which 31 metabolites were determined to be significantly regulated (p ≤ 0.05) after MB exposure. A number of key metabolites revealed by metabolomics analysis include glucose, fructose, citrate, arginine, phenylalanine, and S-adenosylhomocysteine (SAH), suggesting specific modulation of metabolism on carbohydrates, amino acids and peptides, lipids, nucleotide, cofactors and vitamins in HCT-116 CRC cells with MB treatment highly associated with apoptosis triggered by enhanced ROS and activated caspase-3. Conclusion: Our results demonstrate that MB represses CRC cell proliferation by inducing ROS-mediated apoptosis.

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Energy deprivation by silibinin in colorectal cancer cells

Cited by 71 publications

References 54 publications

Target Identification of Grape Seed Extract in Colorectal Cancer Using Drug Affinity Responsive Target Stability (DARTS) Technique: Role of Endoplasmic Reticulum Stress Response Proteins

Target Identification of Grape Seed Extract in Colorectal Cancer Using Drug Affinity Responsive Target Stability (DARTS) Technique: Role of Endoplasmic Reticulum Stress Response Proteins

TAK1 mediates excessive autophagy via p38 and ERK in cisplatin‐induced acute kidney injury

Macranthoidin B Modulates Key Metabolic Pathways to Enhance ROS Generation and Induce Cytotoxicity and Apoptosis in Colorectal Cancer

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