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Cancers
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p53 and Ralbp1 in Carcinogenesis
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p53 and Ralbp1 in Carcinogenesis

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (28 February 2022) | Viewed by 15154

Special Issue Editor

Prof. Dr. Sanjay Awasthi

E-Mail Website
Guest Editor
1. Department of Internal Medicine, Division of Hematology & Oncology, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
2. Department of Surgery, Texas Tech University Health Sciences Center, Lubbock, TX 79415, USA
Interests: glutathione-mediated xenobiotic metabolism and transport of glutathionylated metabolites; oxidative stress; EGFR; Ral; Ras; Rac; Rho; MEK; ERK; MYC; p53; Rb; mTOR; AKT; PI3K; JAK/STAT; VHL; WNT and Ca pathway signaling; epigenetic regulation of gene expression; carcinogenesis; oncogenic and tumor suppressor pathways; transport mediated cancer drug resistance; radiation resistance; cancer therapy (all sites and histologies)

Special Issue Information

Dear Colleagues,  

In humans, genetic lesions that cause loss of TP53, a stress-responsive tumor suppressor protein, causes the Li-Fraumeni hereditary cancer syndrome in humans. Spontaneous cancer develop in nearly all TP53-null mice before 6 months of age. In stark contrast, mice lacking the stress-responsive mercapturic acid pathway ATPase enzyme Ralbp1 (which encodes the 76 kDa protein, RLIP76 aka Rlip) are resistant to carcinogenesis even upon exposure to the most potent chemical carcinogens. We discovered that haploinsufficiency of Rlip can switch off spontaneous carcinogenesis in p53 null mice and cause reversion of their gene promoter methylation defects to wild-type. Because of the pleiotropic functions of both p53 and Rlip, the mechanism of this observations remain unclear. Thus, we have invited scientists studying the various functions and cancer signaling pathways linked to Rlip and p53 to contribute to a discussion that may help elucidate the underlying molecular mechanisms.

Prof. Dr. Sanjay Awasthi
Guest Editor

Manuscript Submission Information

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Keywords

  • Ralbp1/Rlip76Rlip
  • TP53/p53
  • carcinogenesis
  • glutathione
  • oxidative stress
  • 4-hydroxynonenal
  • checkpoint regulation
  • DNA methylation
  • clathrin-dependent endocytosis
  • vesicle trafficking

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Published Papers (5 papers)

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Editorial

Jump to: Research, Review

6 pages, 234 KiB  
Editorial
Haploinsufficiency Interactions of RALBP1 and TP53 in Carcinogenesis
by Sanjay Awasthi
Cancers 2021, 13(2), 255; https://doi.org/10.3390/cancers13020255 - 12 Jan 2021
Cited by 2 | Viewed by 1624
Abstract
Mutagenic environmental chemical or radiant stresses directly damage DNA and amplify the formation of potent endogenous mutagens from lipid peroxidation, leading to cancers that cause millions of deaths and impose enormous financial and social burdens [...] Full article
(This article belongs to the Special Issue p53 and Ralbp1 in Carcinogenesis)

Research

Jump to: Editorial, Review

21 pages, 3041 KiB  
Article
Rlip Depletion Alters Oncogene Transcription at Multiple Distinct Regulatory Levels
by Ashly Hindle, Chhanda Bose, Jihyun Lee, Philip T. Palade, Christopher J. Peterson, P. Hemachandra Reddy, Sanjay Awasthi and Sharda P. Singh
Cancers 2022, 14(3), 527; https://doi.org/10.3390/cancers14030527 - 21 Jan 2022
Viewed by 2385
Abstract
Rlip76 (Rlip) is a multifunctional membrane protein that facilitates the high metabolic rates of cancer cells through the efflux of toxic metabolites and other functions. Rlip inhibition or depletion results in broad-spectrum anti-cancer effects in vitro and in vivo. Rlip depletion effectively suppresses [...] Read more.
Rlip76 (Rlip) is a multifunctional membrane protein that facilitates the high metabolic rates of cancer cells through the efflux of toxic metabolites and other functions. Rlip inhibition or depletion results in broad-spectrum anti-cancer effects in vitro and in vivo. Rlip depletion effectively suppresses malignancy and causes global reversion of characteristic CpG island methylomic and transcriptomic aberrations in the p53-null mouse model of spontaneous carcinogenesis through incompletely defined signaling and transcriptomic mechanisms. The methylome and transcriptome are normally regulated by the concerted actions of several mechanisms that include chromatin remodeling, promoter methylation, transcription factor interactions, and miRNAs. The present studies investigated the interaction of Rlip depletion or inhibition with the promoter methylation and transcription of selected cancer-related genes identified as being affected by Rlip depletion in our previous studies. We constructed novel promoter CpG island/luciferase reporter plasmids that respond only to CpG methylation and transcription factors. We found that Rlip depletion regulated expression by a transcription factor-based mechanism that functioned independently of promoter CpG methylation, lipid peroxidation, and p53 status. Full article
(This article belongs to the Special Issue p53 and Ralbp1 in Carcinogenesis)
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27 pages, 5006 KiB  
Article
Anticancer Activity of Ω-6 Fatty Acids through Increased 4-HNE in Breast Cancer Cells
by Chhanda Bose, Ashly Hindle, Jihyun Lee, Jonathan Kopel, Sahil Tonk, Philip T. Palade, Sharad S. Singhal, Sanjay Awasthi and Sharda P. Singh
Cancers 2021, 13(24), 6377; https://doi.org/10.3390/cancers13246377 - 20 Dec 2021
Cited by 7 | Viewed by 3792
Abstract
Her2-amplified breast cancers resistant to available Her2-targeted therapeutics continue to be a challenge in breast cancer therapy. Dox is the mainstay of chemotherapy of all types of breast cancer, but its usefulness is limited by cumulative cardiotoxicity. Because oxidative stress caused by dox [...] Read more.
Her2-amplified breast cancers resistant to available Her2-targeted therapeutics continue to be a challenge in breast cancer therapy. Dox is the mainstay of chemotherapy of all types of breast cancer, but its usefulness is limited by cumulative cardiotoxicity. Because oxidative stress caused by dox generates the pro-apoptotic Ω-6 PUFA metabolite 4-hydroxynonenal (4-HNE), we surmised that Ω-6 PUFAs would increase the effectiveness of dox chemotherapy. Since the mercapturic acid pathway enzyme RALBP1 (also known as RLIP76 or Rlip) that limits cellular accumulation of 4-HNE also mediates dox resistance, the combination of Ω-6 PUFAs and Rlip depletion could synergistically improve the efficacy of dox. Thus, we studied the effects of the Ω-6 PUFA arachidonic acid (AA) and Rlip knockdown on the antineoplastic activity of dox towards Her2-amplified breast cancer cell lines SK-BR-3, which is sensitive to Her2 inhibitors, and AU565, which is resistant. AA increased lipid peroxidation, 4-HNE generation, apoptosis, cellular dox concentration and dox cytotoxicity in both cell lines while sparing cultured immortalized cardiomyocyte cells. The known functions of Rlip including clathrin-dependent endocytosis and dox efflux were inhibited by AA. Our results support a model in which 4-HNE generated by AA overwhelms the capacity of Rlip to defend against apoptosis caused by dox or 4-HNE. We propose that Ω-6 PUFA supplementation could improve the efficacy of dox or Rlip inhibitors for treating Her2-amplified breast cancer. Full article
(This article belongs to the Special Issue p53 and Ralbp1 in Carcinogenesis)
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19 pages, 2739 KiB  
Article
Haploinsufficiency Interactions between RALBP1 and p53 in ERBB2 and PyVT Models of Mouse Mammary Carcinogenesis
by Sharda P. Singh, Jihyun Lee, Chhanda Bose, Hongzhi Li, Yate-Ching Yuan, Ashly Hindle, Sharad S. Singhal, Jonathan Kopel, Philip T. Palade, Catherine Jones, Rakhshanda L. Rahman and Sanjay Awasthi
Cancers 2021, 13(13), 3329; https://doi.org/10.3390/cancers13133329 - 2 Jul 2021
Cited by 5 | Viewed by 2838
Abstract
We recently reported that loss of one or both alleles of Ralbp1, which encodes the stress-protective protein RLIP76 (Rlip), exerts a strong dominant negative effect on both the inherent cancer susceptibility and the chemically inducible cancer susceptibility of mice lacking one or [...] Read more.
We recently reported that loss of one or both alleles of Ralbp1, which encodes the stress-protective protein RLIP76 (Rlip), exerts a strong dominant negative effect on both the inherent cancer susceptibility and the chemically inducible cancer susceptibility of mice lacking one or both alleles of the tumor suppressor p53. In this paper, we examined whether congenital Rlip deficiency could prevent genetically-driven breast cancer in two transgenic mouse models: the MMTV-PyVT model, which expresses the polyomavirus middle T antigen (PyVT) under control of the mouse mammary tumor virus promoter (MMTV) and the MMTV-Erbb2 model which expresses MMTV-driven erythroblastic leukemia viral oncogene homolog 2 (Erbb2, HER2/Neu) and frequently acquires p53 mutations. We found that loss of either one or two Rlip alleles had a suppressive effect on carcinogenesis in Erbb2 over-expressing mice. Interestingly, Rlip deficiency did not affect tumor growth but significantly reduced the lung metastatic burden of breast cancer in the viral PyVT model, which does not depend on either Ras or loss of p53. Furthermore, spontaneous tumors of MMTV-PyVT/Rlip+/+ mice showed no regression following Rlip knockdown. Finally, mice lacking one or both Rlip alleles differentially expressed markers for apoptotic signaling, proliferation, angiogenesis, and cell cycling in PyVT and Erbb2 breast tumors. Our results support the efficacy of Rlip depletion in suppressing p53 inactivated cancers, and our findings may yield novel methods for prevention or treatment of cancer in patients with HER2 mutations or tumor HER2 expression. Full article
(This article belongs to the Special Issue p53 and Ralbp1 in Carcinogenesis)
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Review

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15 pages, 2960 KiB  
Review
RLIP76: A Structural and Functional Triumvirate
by Jasmine Cornish, Darerca Owen and Helen R. Mott
Cancers 2021, 13(9), 2206; https://doi.org/10.3390/cancers13092206 - 4 May 2021
Cited by 5 | Viewed by 3209
Abstract
RLIP76/RalBP1 is an ATP-dependent transporter of glutathione conjugates, which is overexpressed in various human cancers, but its diverse functions in normal cells, which include endocytosis, stress response and mitochondrial dynamics, are still not fully understood. The protein can be divided into three distinct [...] Read more.
RLIP76/RalBP1 is an ATP-dependent transporter of glutathione conjugates, which is overexpressed in various human cancers, but its diverse functions in normal cells, which include endocytosis, stress response and mitochondrial dynamics, are still not fully understood. The protein can be divided into three distinct regions, each with its own structural properties. At the centre of the protein are two well-defined domains, a GTPase activating protein domain targeting Rho family small G proteins and a small coiled-coil that binds to the Ras family small GTPases RalA and RalB. In engaging with Rho and Ral proteins, RLIP76 bridges these two distinct G protein families. The N-terminal region is predicted to be disordered and is rich in basic amino acids, which may mediate membrane association, consistent with its role in transport. RLIP76 is an ATP-dependent transporter with ATP-binding sites within the N-terminus and the Ral binding domain. Furthermore, RLIP76 is subject to extensive phosphorylation, particularly in the N-terminal region. In contrast, the C-terminal region is thought to form an extensive coiled-coil that could mediate dimerization. Here, we review the structural features of RLIP76, including experimental data and computational predictions, and discuss the implications of its various post-translational modifications. Full article
(This article belongs to the Special Issue p53 and Ralbp1 in Carcinogenesis)
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