The HBx protein of hepatitis B virus confers resistance against nucleolar stress and anti‐cancer drug‐induced p53 expression

Kapoor, Neetu Rohit; Ahuja, Richa; Shukla, Surendra K.; Kumar, Vijay

doi:10.1016/j.febslet.2013.03.004

Cited by 21 publications

(15 citation statements)

References 30 publications

(56 reference statements)

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“…Several previous studies found that HBx induced multiple chemotherapeutic drugs resistance through regulating various signaling factors, such as p53 and NF-ĸB (7,26,27). In our present study, the drug resistance activity induced by HBx was consistent with the results of several previous studies (7,26,27); we identified that signaling pathways involving RhoA, ROCK1 and p38 MAPK are associated with HBxinduced autophagy. In addition, UA, a pentacyclic triterpenoid acid known to possess a hepatoprotective function, demonstrated a suppression effect on HBx.…”

Section: Discussionsupporting

confidence: 92%

“…UA. Previous studies found that HBx endowed multiple chemotherapeutic drugs resistance through modulation of various cellular factors, for example, p53 tumor suppressor and NF-ĸB (7,26,27). To further understand the therapeutic potential of UA, the drug sensitivity IC 50 was evaluated in Huh7 cells treated with three anti-cancer DNA-damage agents in clinical use.…”

Section: Reversion Of Hbx-mediated Dna-damage Drug Resistance Bymentioning

confidence: 99%

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Ursolic Acid Suppresses Hepatitis B Virus X Protein-mediated Autophagy and Chemotherapeutic Drug Resistance

Chang

Lin²,

Hsu

et al. 2016

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Hepatitis B virus X (HBx) protein is a multifunctional oncoprotein that affects diverse cell activities via regulation of various host cell signaling pathways. The current investigation demonstrated that ursolic acid (UA), a pentacyclic triterpenoid, protected hepatoma cells and reduced HBx-mediated autophagy through modulation of Ras homolog gene family member A (RhoA). Low-level ectopic HBx expression in Huh7 cells induced more significant autophagosome formation than high-level HBx expression. HBx activated beclin-1 promoter and enhanced the beclin-1 protein expression under low HBx expression. Transcription factor AP-1 played an essential function in HBx-mediated beclin-1 promoter activation. Inhibition of RhoA and its downstream effector Rho-associated coiled-coil-containing protein kinase 1 (ROCK1) alleviated HBx-mediated autophagy significantly. Transiently-expressed HBx elicited an increased RhoA-GTP level, as well as phospho-ROCK1 transient accumulation. Utilization of transactivation-deficient HBx demonstrated that the transactivation activity of HBx is required for autophagy induction. Furthermore, UA suppressed HBx-mediated RhoA activation, beclin-1 promoter activation and subsequent autophagy induction, while, most importantly, reversed HBx-induced anti-cancer drug resistance.

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Section: Discussionsupporting

confidence: 92%

Section: Reversion Of Hbx-mediated Dna-damage Drug Resistance Bymentioning

confidence: 99%

Ursolic Acid Suppresses Hepatitis B Virus X Protein-mediated Autophagy and Chemotherapeutic Drug Resistance

Chang

Lin²,

Hsu

et al. 2016

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“…The modifications of RPs that are involved in the RPs–MDM2–p53 pathway deserve further exploration. Interestingly, the HBx (Hepatitis B virus X) oncoprotein confers nucleolar stress induced p53 expression by disrupting the interaction between L11 and MDM2, suggesting the possible inactivation of the L11–MDM2–p53 pathway by the HBx oncoprotein in hepatocellular carcinogenesis. However, the relationship between defective ribosome biogenesis and cancer is complicated and not fully understood.…”

Section: Discussionmentioning

confidence: 99%

Ribosomal Proteins and Human Diseases: Pathogenesis, Molecular Mechanisms, and Therapeutic Implications

Wang

Nag

Zhang

et al. 2014

Medicinal Research Reviews

179

154

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Ribosomes are essential components of the protein synthesis machinery. The process of ribosome biogenesis is well organized and tightly regulated. Recent studies have shown that ribosomal proteins (RPs) have extraribosomal functions that are involved in cell proliferation, differentiation, apoptosis, DNA repair, and other cellular processes. The dysfunction of RPs has been linked to the development and progression of hematological, metabolic, and cardiovascular diseases and cancer. Perturbation of ribosome biogenesis results in ribosomal stress, which triggers activation of the p53 signaling pathway through RPs-MDM2 interactions, resulting in p53-dependent cell cycle arrest and apoptosis. RPs also regulate cellular functions through p53-independent mechanisms. We herein review the recent advances in several forefronts of RP research, including the understanding of their biological features and roles in regulating cellular functions, maintaining cell homeostasis, and their involvement in the pathogenesis of human diseases. We also highlight the translational potential of this research for the identification of molecular biomarkers, and in the discovery and development of novel treatments for human diseases.

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“…In fact, in addition to their role in assembling with rRNA to construct ribosomes for new protein synthesis, ribosomal proteins are known to have many extraribosomal roles [12]–[14]. One of the ribosomal proteins, ribosomal protein S27-like (RPS27L), was reported to be downregulated in feces and tumor tissues of some late-stage CRC patients [15], [16].…”

Section: Introductionmentioning

confidence: 99%

Ribosomal Protein S27-Like in Colorectal Cancer: A Candidate for Predicting Prognoses

et al. 2013

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BackgroundThe development and progression of colorectal cancer (CRC) involve a complex process of multiple genetic changes. Tumor suppressor p53 is capable of determining the fate of CRC cells. However, the role of a p53-inducible modulator, ribosomal protein S27-like (RPS27L), in CRC is unknown.MethodsHere, the differential expression of RPS27L was examined in the feces and colonic tissues of CRC patients, to explore its possible correlation with patient survival and to investigate the cellular mechanisms underlying their clinical outcomes. Eighty intermediate-stage CRC patients (42 at stage II and 38 at stage III) were divided into two groups according to their fecal RPS27L mRNA levels. The survival probabilities of the groups were estimated using the Kaplan–Meier method. The RPS27L protein in the colonic tissues of stage III patients with different prognoses was further examined immunohistochemically. RPS27L expression in LoVo cells was manipulated to examine the possible cellular responses in vitro.ResultsElevated RPS27L expression, in either feces or tissues, was related to a better prognosis. In vitro, RPS27L-expressing LoVo cells ceased DNA synthesis and apoptotic activity while the expression of their DNA repair molecules was upregulated.ConclusionsElevated RPS27L may improve the prognoses of certain CRC patients by enhancing the DNA repair capacity of their colonic cells, and can be determined in feces. By integrating clinical, molecular, and cellular data, our study demonstrates that fecal RPS27L may be a useful index for predicting prognoses and guiding personalized therapeutic strategies, especially in patients with intermediate-stage CRC.

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The HBx protein of hepatitis B virus confers resistance against nucleolar stress and anti‐cancer drug‐induced p53 expression

Cited by 21 publications

References 30 publications

Ursolic Acid Suppresses Hepatitis B Virus X Protein-mediated Autophagy and Chemotherapeutic Drug Resistance

Ursolic Acid Suppresses Hepatitis B Virus X Protein-mediated Autophagy and Chemotherapeutic Drug Resistance

Ribosomal Proteins and Human Diseases: Pathogenesis, Molecular Mechanisms, and Therapeutic Implications

Ribosomal Protein S27-Like in Colorectal Cancer: A Candidate for Predicting Prognoses

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