Anti-Cancer Effect of HIV-1 Viral Protein R on Doxorubicin Resistant Neuroblastoma

Zhao, Yuqi; Dong, Liang; Li, G e; Larrimore, Christopher; Mirkin, Bernard L.

doi:10.1371/journal.pone.0011466

Cited by 12 publications

(11 citation statements)

References 43 publications

(48 reference statements)

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“…1A ). Although we have focused on the effects of Tat as an example of how HIV proteins might dysregulate cell cycle activation and trigger neurotoxicity, we recognize that other HIV proteins such as nef, vif, and vpr might also dysregulate CDKs [117, 118]. …”

Section: Resultsmentioning

confidence: 99%

Mechanisms of HIV-1 Tat Neurotoxicity via CDK5 Translocation and Hyper-Activation: Role in HIV-Associated Neurocognitive Disorders

Fields¹,

Dumaop²,

Crews³

et al. 2015

CHR

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The advent of more effective antiretroviral therapies has reduced the frequency of HIV dementia, however the prevalence of milder HIV associated neurocognitive disorders [HAND] is actually rising. Neurodegenerative mechanisms in HAND might include toxicity by secreted HIV-1 proteins such as Tat, gp120 and Nef that could activate neuro-inflammatory pathways, block autophagy, promote excitotoxicity, oxidative stress, mitochondrial dysfunction and dysregulation of signaling pathways. Recent studies have shown that Tat could interfere with several signal transduction mechanisms involved in cytoskeletal regulation, cell survival and cell cycle re-entry. Among them, Tat has been shown to hyper-activate cyclin-dependent kinase [CDK] 5, a member of the Ser/Thr CDKs involved in cell migration, angiogenesis, neurogenesis and synaptic plasticity. CDK5 is activated by binding to its regulatory subunit, p35 or p39. For this manuscript we review evidence showing that Tat, via calcium dysregulation, promotes calpain-1 cleavage of p35 to p25, which in turn hyper-activates CDK5 resulting in abnormal phosphorylation of downstream targets such as Tau, collapsin response mediator protein-2 [CRMP2], doublecortin [DCX] and MEF2. We also present new data showing that Tat interferes with the trafficking of CDK5 between the nucleus and cytoplasm. This results in prolonged presence of CDK5 in the cytoplasm leading to accumulation of aberrantly phosphorylated cytoplasmic targets [e.g.: Tau, CRMP2, DCX] that impair neuronal function and eventually lead to cell death. Novel therapeutic approaches with compounds that block Tat mediated hyper-activation of CDK5 might be of value in the management of HAND.

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Section: Resultsmentioning

confidence: 99%

Mechanisms of HIV-1 Tat Neurotoxicity via CDK5 Translocation and Hyper-Activation: Role in HIV-Associated Neurocognitive Disorders

Fields¹,

Dumaop²,

Crews³

et al. 2015

CHR

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show abstract

“…Blockage of NF-κB signaling can delay mitotic entry and keep cells at the G2 phase (40). Based on previous studies, protein phosphatase 2A (PP2A), a serine/threonine phosphatase, could play an essential role in G2 cell cycle arrest induced by Vpr (15,41). PP2A can dephosphorylate and modulate the activity of IKKβ (42), one of two catalytic subunits of IKK.…”

Section: Discussionmentioning

confidence: 99%

“…Expression of Vpr protein was able to induce cell cycle arrest and apoptosis. Therefore, many studies have analyzed the potential antitumor activity of this molecule both in vitro and in vivo (7)(8)(9)(10)(11)(12)(13)(14)(15). Previous studies have shown that the Vpr protein appears to preferentially inhibit the growth of rapidly dividing tumor cells, but does not affect the normal cells regardless of changes in p53 expression (7)(8)(9)15 Abbreviations: Ad, adenovirus; GFP, green fluorescent protein; Vpr, viral protein R; MOI, multiplicity of infection; MTT, 3-(4,5)-dimethylthiazo(-2-yl)-2,5-di-phenyltetrazolium bromide; PI, propidium iodide; NF-κB, nuclear factor-κB…”

mentioning

confidence: 99%

HIV-1 viral protein R (Vpr) induction of apoptosis and cell cycle arrest in multidrug-resistant colorectal cancer cells

Zhang

Wang

et al. 2012

Oncol Rep

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Abstract. Colorectal cancer is a significant health problem, and the advanced stages of the disease have a low response rate to chemotherapy and easily acquire chemoresistance. HIV-1 viral protein R (Vpr) has been shown to possess inhibitory effects on various malignant cells in vivo and in vitro. In this study, an Ad-Vpr construct was used to infect the multidrug-resistant human colorectal cancer HCT-8/5-FU(MDR) cell line in vitro for cell viability, apoptosis, gene expression and gene activity using the MTT, flow cytometry, immunoblotting and gel shift assays, respectively. The data showed that Ad-Vpr significantly reduced HCT-8/5-FU(MDR) cell viability in a dose-and time-dependent manner. Ad-Vpr infection promoted HCT-8/5-FU(MDR) cells to undergo apoptosis and to arrest at the G2 phase of the cell cycle. The G2 cell cycle protein Cyclin B1 accumulated in the cells after Ad-Vpr infection. Furthermore, Ad-Vpr induced activation of caspase-3 and -9, but not caspase-8, in HCT-8/5-FU(MDR) cells. Ad-Vpr suppressed expression of the Bcl-xl protein, but upregulated Bax expression and cytochrome c release from the mitochondria in HCT-8/5-FU(MDR) cells. Ad-Vpr infection also resulted in a time-dependent decrease in nuclear translocation of NF-κB/p65 protein and p65 DNA-binding activity in HCT-8/5-FU(MDR) cells. The data from the current study provide mechanistic insights into understanding the molecular basis and utility of Ad-Vpr as a novel anticancer agent for multidrug resistance in human colorectal cancer. IntroductionColorectal cancer is a significant health problem in the world, and is the third most common cancer in women and the fourth most common in men. More than half a million patients with colorectal cancer die of the disease annually worldwide (1,2). To date, surgical intervention is the most effective tool to cure colorectal cancer, whereas chemotherapy is another important means to treat colorectal cancer, especially for advanced staged disease. In those patients, chemotherapy appears to be the only therapeutic modality and offers some benefit. For chemotherapy, 5-fluorouracil (5-FU)-based regimens are the most common choice for patients. The combination of 5-FU with irinotecan and oxaliplatin has significantly improved the response rate of colorectal cancer patients. Additionally, combination regimens of 5-FU with irinotecan have been evaluated as the first-line therapeutic selection for advanced colorectal cancer with a response rate of 30-50% and an overall survival of 14-20 months (3,4). However, the response rate for these advanced targeted therapies and third-generation chemotherapies remains low (5). The reason may be due to innate and acquired chemoresistance (6) of colorectal cancer, which often leads to relapse and poor patient prognosis. Thus, a more aggressive and effective therapy to control colorectal cancer is imperative.To this end, our research focuses on the viral protein R (Vpr), which is an accessory protein and plays an important role in the regulation of nuclear import of the HIV-1 ...

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“…The Adenoviral (Adv) Vpr construct was generated in this laboratory 16,17 by using the AdEasy Adenoviral Vector system (Cat#: 240009;…”

Section: Adenoviral Constructs and Cell Transductionmentioning

confidence: 99%

HIV-1 Vpr-induced Proinflammatory Response and Apoptosis are Mediated through the Sur1-Trpm4 Channel in Astrocytes

Makar

Gerzanich

et al. 2020

Preprint

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There are about 38 million people currently living with HIV/AIDS worldwide. Successful treatment with combinational antiretroviral therapies (cART) can eliminate active replicating viruses and prolong lives to nearly normal lifespans. However, the new challenge faced by more than half of those HIV-infected and aging patients is chronic CNS neuroinflammation, which leads to HIVassociated neurocognitive disorders (HAND). While severe and progressive HAND has decreased significantly due to cART, chronic HAND often persists, resulting in high rates of delirium, dementia and depression that could lead to suicide. Indeed, the risk of suicide mortality in HIV-infected persons is significantly higher than in HIV-uninfected counterparts. Nevertheless, the mechanism of neuropathogenesis underlying HAND is not well understood. HAND is typically characterized by HIV-mediated glial neuroinflammation and neurotoxicity. Interestingly, the severity of some HAND does not always correlate with the levels of HIV, but rather with glial activation, suggesting other HIV-associated factors, not the whole virus per se, contribute to those HAND. HIV-1 viral protein R (Vpr) might be one of those viral factors, because Vpr induces neuroinflammation and causes neuronal apoptosis. The objective of this study was to delineate the specific role(s) of Vpr in activation of host neuroinflammation and neurotoxicity, as well as its contribution to HAND.In this report, we show correlations between HIV expression and activation of proinflammatory markers (TLR4, TNFα, and NFκB) and the Sur1-Trpm4 channel in astrocytes of HIV-infected postmortem human and transgenic mouse brain tissues. We further show that Vpr alone activate the same set of proinflammatory markers in an astrocytic cell line SNB19. Vpr-induced host cell proinflammatory responses result in apoptotic cell death. Together, our data suggest that HIV-1 Vpr-induced proinflammatory response and apoptotic cell death are mediated through the Sur1-Trpm4 channel in astrocytes.

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Anti-Cancer Effect of HIV-1 Viral Protein R on Doxorubicin Resistant Neuroblastoma

Cited by 12 publications

References 43 publications

Mechanisms of HIV-1 Tat Neurotoxicity via CDK5 Translocation and Hyper-Activation: Role in HIV-Associated Neurocognitive Disorders

Mechanisms of HIV-1 Tat Neurotoxicity via CDK5 Translocation and Hyper-Activation: Role in HIV-Associated Neurocognitive Disorders

HIV-1 viral protein R (Vpr) induction of apoptosis and cell cycle arrest in multidrug-resistant colorectal cancer cells

HIV-1 Vpr-induced Proinflammatory Response and Apoptosis are Mediated through the Sur1-Trpm4 Channel in Astrocytes

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