Cambogin Induces Caspase-Independent Apoptosis through the ROS/JNK Pathway and Epigenetic Regulation in Breast Cancer Cells

Shen, Kaikai; Xie, Jianling; Wang, Hua; Zhang, Hong; Yu, Mengyuan; Lu, Fangfang; Tan, Hongsheng; Hong, Xu

doi:10.1158/1535-7163.mct-14-1048

Cited by 38 publications

(37 citation statements)

References 42 publications

(53 reference statements)

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“…We have reported previously [21] that cambogin (chemical structure shown in Figure 1A) strongly inhibits cell proliferation in several breast cancer cell lines, including MCF-7 (ER + PR + HER2 − ), SK-BR-3 (ER − PR − HER2 + ) and MDA-MB-468 (ER − PR − HER2 − , also known as TNBC (triple negative breast cancer)). As shown in Figure 1B, cambogin (0-10 μM) treatment led to a reduction in MCF-7 cell viability in a dose-dependent manner, which can be achieved with a concentration as low as 1.25 μM, whereas at 10 μM it produced the maximal inhibition.…”

Section: Resultsmentioning

confidence: 99%

“…Polycyclic polyprenylated acylphloroglucinols (PPAPs), one of the main bioactive components, are known to possess anticancer activities, including the induction of apoptosis, the inhibition of proliferation, and the prevention of cancer metastasis and tumor angiogenesis [19-21]. One of the mechanisms by which PPAPs exert anti-tumor effect is via elevating the levels of ROS [21, 22]. Cambogin is a bioactive PPAP isolated from the branches of Garcinia esculenta [23].…”

Section: Introductionmentioning

confidence: 99%

“…Cambogin is a bioactive PPAP isolated from the branches of Garcinia esculenta [23]. Previously we have shown that cambogin induces breast adenocarcinoma cell apoptosis via ROS-mediated increases in Bax/Bcl-2 ratio and the nuclear import of apoptosis inducing factor (AIF), in parallel with the stimulation of ASK1-MKK4/MKK7-JNK/SAPK signaling cascade [21]. However, the underlying mechanism of how cambogin promotes ROS formation remains elusive.…”

Section: Introductionmentioning

confidence: 99%

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Cambogin exerts anti-proliferative and pro-apoptotic effects on breast adenocarcinoma through the induction of NADPH oxidase 1 and the alteration of mitochondrial morphology and dynamics

Shen

Xie

et al. 2016

Oncotarget

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Cambogin, a bioactive polycyclic polyprenylated acylphoroglucinol (PPAP) derived from the Garcinia genus, possesses proapoptotic effect in medulloblastoma and breast cancer cells. We have previously demonstrated that the proapoptotic effect of cambogin is driven by the production of reactive oxygen species (ROS). Here we have shown that the inhibitory effect of cambogin on cell proliferation is associated with the loss of mitochondrial transmembrane potential (ΔΨm) and mitochondrial fragmentation. Cambogin also promotes the mutual complex formation of the membrane-bound subunit p22phox of NADPH oxidase 1 (NOX1), as well as the phosphorylation of the cytosolic subunit p47phox, subsequently enhancing membrane-bound NOX1 activity, which leads to increases in intracellular and mitochondrial levels of O2.- and H2O2. Pharmacological inhibition of NOX1 using apocynin (pan-NOX inhibitor), ML171 (NOX1 inhibitor) or siRNA against NOX1 prevents the increases in O2.- and H2O2 levels and the anti-proliferative effect of cambogin. Antioxidants, including SOD (superoxide dismutase), CAT (catalase) and EUK-8, are also able to restore cell viability in the presence of cambogin. Besides, cambogin increases the dissociation of thioredoxin-1 (Trx1) from ASK1, switching the inactive form of ASK1 to the active kinase, subsequently leads to the phosphorylation of JNK/SAPK, which is abolished upon ML171 treatment. The proapoptotic effect of cambogin in breast cancer cells is also aggravated upon knocking down Trx1 in MCF-7 cells. Taken in conjunction, these data indicate that the anti-proliferative and pro-apoptotic effect of cambogin is mediated via inducing NOX1-dependent ROS production and the dissociation of ASK1 and Trx1.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cambogin exerts anti-proliferative and pro-apoptotic effects on breast adenocarcinoma through the induction of NADPH oxidase 1 and the alteration of mitochondrial morphology and dynamics

Shen

Xie

et al. 2016

Oncotarget

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“…Colony formation assay was performed as described previously (25). Tumor cells were seeded into 6-well plates and cultured overnight.…”

Section: Colony Formation Assaymentioning

confidence: 99%

Lycorine Promotes Autophagy and Apoptosis via TCRP1/Akt/mTOR Axis Inactivation in Human Hepatocellular Carcinoma

Qiu

Pang

et al. 2017

Molecular Cancer Therapeutics

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Lycorine is a multifunctional bioactive compound, and it possesses potential anticancer activities. However, little is known about the underlying mechanism. In this research, we have found that lycorine significantly induces the apoptotic and autophagic capacities of hepatocellular carcinoma (HCC) cells in vitro and in vivo. Treatment with specific autophagy inhibitor (3-methyladenine/Bafilomycin A1) or knockdown of LC-3B/Atg5 by siRNA drastically enhances the apoptotic cell death effect by facilitating the switch from autophagy to apoptosis. Molecular validation mechanistically demonstrates that lycorine-induced apoptosis and autophagy in HCC cells is associated with decreased protein levels of tongue cancer resistance-associated protein 1 (TCRP1), and we further find that inhibition of TCRP1 decreases phosphorylation level of Akt and represses Akt/mTOR signaling. Finally, lycorineinduced apoptosis and autophagy suppress the growth of xenograft hepatocellular tumors without remarkable toxicity. Our results elucidate a novel molecular mechanism whereby lycorine promotes apoptosis and autophagy through the TCRP1/Akt/mTOR pathway in HCC. Our results reveal that lycorine might be a potential therapeutic agent for the treatment of HCC.

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“…It is well known that ROS generation is closely associated with early stages of apoptosis and mitochondrial dysfunction (36). Earlier reports suggest that ROS generation, together with Cyt C release from mitochondria, promote cell death (37, 38). This results in increased permeability of the outer mitochondrial membrane, decreasing transmembrane potential, and activation of AIF (32) eventually inducing caspase-independent apoptosis (39).…”

Section: Discussionmentioning

confidence: 99%

mda-7/IL-24 Induces Cell Death in Neuroblastoma through a Novel Mechanism Involving AIF and ATM

et al. 2016

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Advanced stages of neuroblastoma, the most common extracranial malignant solid tumor of the central nervous system in infants and children, are refractive to therapy. Ectopic expression of melanoma differentiation associated gene-7/Interleukin-24 (mda-7/IL-24) promotes broad-spectrum antitumor activity in vitro, in vivo in pre-clinical animal models and in a Phase I clinical trial in patients with advanced cancers, without harming normal cells. mda-7/IL-24 exerts cancer-specific toxicity (apoptosis or toxic autophagy) by promoting ER stress and modulating multiple signal transduction pathways regulating cancer cell growth, invasion, metastasis, survival and angiogenesis. To enhance cancer-selective expression and targeted anti-cancer activity of mda-7/IL-24 we created a tropism-modified Cancer Terminator Virus (Ad.5/3-CTV), which selectively replicates in cancer cells producing robust expression of mda-7/IL-24. We now show that Ad.5/3-CTV induces profound neuroblastoma anti-proliferative activity and apoptosis in a caspase 3/9-independent manner both in vitro and in vivo in a tumor xenograft model. Ad.5/3-CTV promotes these effects through a unique pathway involving apoptosis inducing factor (AIF) translocation into the nucleus. Inhibiting AIF rescued neuroblastoma cells from Ad.5/3-CTV-induced cell death, whereas pan-caspase inhibition failed to promote survival. Ad.5/3-CTV infection of neuroblastoma cells increased ATM phosphorylation instigating nuclear translocation and increased γ–H2AX, triggering nuclear translocation and intensified expression of AIF. These results were validated further using two ATM small molecule inhibitors that attenuated PARP cleavage by inhibiting γ–H2AX, which in turn inhibited AIF changes in Ad.5/3-CTV-infected neuroblastoma cells. Taken together, we elucidate a novel pathway for mda-7/IL-24-induced caspase-independent apoptosis in neuroblastoma cells mediated through modulation of AIF, ATM and γ–H2AX.

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Cambogin Induces Caspase-Independent Apoptosis through the ROS/JNK Pathway and Epigenetic Regulation in Breast Cancer Cells

Cited by 38 publications

References 42 publications

Cambogin exerts anti-proliferative and pro-apoptotic effects on breast adenocarcinoma through the induction of NADPH oxidase 1 and the alteration of mitochondrial morphology and dynamics

Cambogin exerts anti-proliferative and pro-apoptotic effects on breast adenocarcinoma through the induction of NADPH oxidase 1 and the alteration of mitochondrial morphology and dynamics

Lycorine Promotes Autophagy and Apoptosis via TCRP1/Akt/mTOR Axis Inactivation in Human Hepatocellular Carcinoma

mda-7/IL-24 Induces Cell Death in Neuroblastoma through a Novel Mechanism Involving AIF and ATM

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