Etoposide‐resistant HT‐29 human colon carcinoma cells during glucose deprivation are sensitive to piericidin A, a GRP78 down‐regulator

Hwang, Ji‐Hwan; Kim, Ju‐Young; Cha, Mi-Ran; Ryoo, In‐Ja; Choo, Soo‐Jin; Cho, Sung Min; Tsukumo, Yoshinori; Tomida, Akihiro; Shin‐ya, Kazuo; Hwang, Yong-Il; Yoo, Ick Dong; Park, Hae-Ryong

doi:10.1002/jcp.21308

Cited by 40 publications

(29 citation statements)

References 45 publications

(52 reference statements)

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“…Examples are arctigenin [167], deoxyverrucosidin [168], efrapeptin J [169], analogs of JBIR [170], piericidin A [171], prunustatin A [172], pyrvinium [173], rottlerin [174], valinomycin [175], and versipelostatin [176]. Collectively, these compounds are considered GRP78 downregulators, because they were shown to block the adaptive induction of GRP78 transcription in response to hypoglycemia.…”

Section: Er Stress In Cancermentioning

confidence: 99%

Endoplasmic Reticulum Stress: Its Role in Disease and Novel Prospects for Therapy

2012

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The endoplasmic reticulum (ER) is a multifunctional organelle required for lipid biosynthesis, calcium storage, and protein folding and processing. A number of physiological and pathological conditions, as well as a variety of pharmacological agents, are able to disturb proper ER function and thereby cause ER stress, which severely impairs protein folding and therefore poses the risk of proteotoxicity. Specific triggers for ER stress include, for example, particular intracellular alterations (e.g., calcium or redox imbalances), certain microenvironmental conditions (e.g., hypoglycemia, hypoxia, and acidosis), high-fat and high-sugar diet, a variety of natural compounds (e.g., thapsigargin, tunicamycin, and geldanamycin), and several prescription drugs (e.g., bortezomib/Velcade, celecoxib/Celebrex, and nelfinavir/Viracept). The cell reacts to ER stress by initiating a defensive process, called the unfolded protein response (UPR), which is comprised of cellular mechanisms aimed at adaptation and safeguarding cellular survival or, in cases of excessively severe stress, at initiation of apoptosis and elimination of the faulty cell. In recent years, this dichotomic stress response system has been linked to several human diseases, and efforts are underway to develop approaches to exploit ER stress mechanisms for therapy. For example, obesity and type 2 diabetes have been linked to ER stress-induced failure of insulin-producing pancreatic beta cells, and current research efforts are aimed at developing drugs that ameliorate cellular stress and thereby protect beta cell function. Other studies seek to pharmacologically aggravate chronic ER stress in cancer cells in order to enhance apoptosis and achieve tumor cell death. In the following, these principles will be presented and discussed.

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Section: Er Stress In Cancermentioning

confidence: 99%

Endoplasmic Reticulum Stress: Its Role in Disease and Novel Prospects for Therapy

2012

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“…Moreover, Grp-78 expression is affected by a number of factors. For example, glucose deprivation results in upregulation of Grp-78 in human cancer cells [32], overexpression of c-Myb can induce the endogenous Grp-78 gene [33], and Grp-78 is upregulated by endosulfan in A549 cells [34]. Thus, STAT3 signaling pathway might play a role during tumor genesis and development via direct or indirect regulation of Grp-78, but this relationship is still in need of further study.…”

Section: Hcc Cell Growth By Mtt Assaymentioning

confidence: 99%

Silencing STAT3 may inhibit cell growth through regulating signaling pathway, telomerase, cell cycle, apoptosis and angiogenesis in hepatocellular carcinoma: potential uses for gene therapy

Wang

Liu²,

B³

et al. 2011

neo

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The genesis and development of hepatocellular carcinoma (HCC) is related to the abnormity of signaling pathway, telomerase, cell cycle, apoptosis, angiogenesis, and others, in which STAT3 signaling pathway plays a key role. The HCC cell line HepG 2 was transfected with small interfering RNA (siRNA) directed against STAT3. After 72 h, cell growth and cycle were analysed by MTT and Flow cytometry. Then, the protein was extracted and the protein expression of STAT3, Smad3, p44/42, TERT, caspase-3, XIAP, Grp-78, HSP-27, MMP-2, MMP-9, VEGF-A, cyclin A, and cyclin E was detected by Western blot. After the transfection, HCC cell growth was inhibited during the 24-72 h time period and the cell cycle was arrested in G0/G1. STAT3 protein expression was inhibited at 72 h after the transfection. Interestingly, Smad3, p-caspase-3, p-p44/42, Grp78, cyclin A, and cyclin E protein expression was increased at 72 h, while TERT, caspase-3, XIAP, MMP-2, MMP-9, and VEGF-A protein expression decreased at 72 h. However, P44/42, and HSP27 protein expression showed no change following transfection. The results demonstrated that STAT3 signaling pathway may participate in HCC genesis and development through regulating the protein expression of other signaling pathway, telomerase, apoptosis, cell cycle and angiogenesis; thereby, blockade of the Stat3 pathway represents a potential strategy for future treatment.

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“…Other members of this group are arctigenin [15], biguanides (metformin, phenformin, buformin) [16], deoxyverrucosidin [17], efrapeptin J [18], analogs of JBIR [19], piericidin A [20], prunustatin A [21], pyrvinium [22], rottlerin [23], valinomycin [24], and versipelostatin [25]. Because GRP78 plays an important role in tumorigenesis, such inhibitors might harbor cancer therapeutic potential.…”

Section: Discussionmentioning

confidence: 99%

Repositioning of Verrucosidin, a Purported Inhibitor of Chaperone Protein GRP78, as an Inhibitor of Mitochondrial Electron Transport Chain Complex I

et al. 2013

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Verrucosidin (VCD) belongs to a group of fungal metabolites that were identified in screening programs to detect molecules that preferentially kill cancer cells under glucose-deprived conditions. Its mode of action was proposed to involve inhibition of increased GRP78 (glucose regulated protein 78) expression during hypoglycemia. Because GRP78 plays an important role in tumorigenesis, inhibitors such as VCD might harbor cancer therapeutic potential. We therefore sought to characterize VCD’s anticancer activity in vitro. Triple-negative breast cancer cell lines MDA-MB-231 and MDA-MB-468 were treated with VCD under different conditions known to trigger increased expression of GRP78, and a variety of cellular processes were analyzed. We show that VCD was highly cytotoxic only under hypoglycemic conditions, but not in the presence of normal glucose levels, and VCD blocked GRP78 expression only when glycolysis was impaired (due to hypoglycemia or the presence of the glycolysis inhibitor 2-deoxyglucose), but not when GRP78 was induced by other means (hypoxia, thapsigargin, tunicamycin). However, VCD’s strictly hypoglycemia-specific toxicity was not due to the inhibition of GRP78. Rather, VCD blocked mitochondrial energy production via inhibition of complex I of the electron transport chain. As a result, cellular ATP levels were quickly depleted under hypoglycemic conditions, and common cellular functions, including general protein synthesis, deteriorated and resulted in cell death. Altogether, our study identifies mitochondria as the primary target of VCD. The possibility that other purported GRP78 inhibitors (arctigenin, biguanides, deoxyverrucosidin, efrapeptin, JBIR, piericidin, prunustatin, pyrvinium, rottlerin, valinomycin, versipelostatin) might act in a similar GRP78-independent fashion will be discussed.

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Etoposide‐resistant HT‐29 human colon carcinoma cells during glucose deprivation are sensitive to piericidin A, a GRP78 down‐regulator

Cited by 40 publications

References 45 publications

Endoplasmic Reticulum Stress: Its Role in Disease and Novel Prospects for Therapy

Endoplasmic Reticulum Stress: Its Role in Disease and Novel Prospects for Therapy

Silencing STAT3 may inhibit cell growth through regulating signaling pathway, telomerase, cell cycle, apoptosis and angiogenesis in hepatocellular carcinoma: potential uses for gene therapy

Repositioning of Verrucosidin, a Purported Inhibitor of Chaperone Protein GRP78, as an Inhibitor of Mitochondrial Electron Transport Chain Complex I

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