RLIP: An existential requirement for breast carcinogenesis

Singhal, Sharad S.; Salgia, Ravi; Singhal, Sulabh; Horne, David; Awasthi, Yogesh C.

doi:10.1016/j.bbcan.2019.02.001

Cited by 10 publications

(7 citation statements)

References 69 publications

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“…TNF-α, PKC-α, fibronectin, CDK4, cyclin B1, and CD31were inhibited by 2HF, while BIM and pAMPK were activated. The pattern of signaling inhibition in melanoma upon treatment with 2HF is similar to that observed previously upon Rlip inhibition or depletion in renal cell carcinoma, breast cancer, neuroblastoma, prostate cancer, pancreatic adenocarcinoma, non-small cell and small cell lung carcinoma, and lymphoma [23,25,26,31,63,64,65,66]. This finding strengthens the assertion that 2HF inhibits melanoma growth through Rlip inhibition.…”

Section: Discussionsupporting

confidence: 86%

Topical 2′-Hydroxyflavanone for Cutaneous Melanoma

Bose

Singh

Igid

et al. 2019

Cancers

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2′-hydroxyflavanone (2HF) is a dietary flavonoid with anticancer activity towards multiple cancers. Here, we report that topically applied 2HF inhibits the growth of intradermal implants of melanoma in immunocompetent mice. 2HF induced apoptosis and inhibited the growth of the human SK-MEL-24 as well as murine B16-F0 and B16-F10 melanoma cell lines in vitro. Apoptosis was associated with depletion of caspase-3, caspase-9, and PARP1 in B16-F0 and SK-MEL-24 cells. Caspase-9 and MEKK-15 were undetected even in untreated B16-F10 cells. Signaling proteins TNFα, and phospho-PDGFR-β were depleted in all three cell lines; MEKK-15 was depleted by 2HF in SK-MEL-24 cells. 2HF enhanced sunitinib (an MEK and PDGFR-β inhibitor) and AZD 2461 (a PARP1 inhibitor) cytotoxicity. 2HF also depleted the Ral-regulated, stress-responsive, antiapoptotic endocytic protein RLIP76 (RALBP1), the inhibition of which has previously been shown to inhibit B16-F0 melanoma growth in vivo. Functional inhibition of RLIP76 was evident from inhibition of epidermal growth factor (EGF) endocytosis by 2HF. We found that topically applied 2HF–Pluronic Lecithin Organogel (PLO) gel inhibited B16-F0 and B16-F10 tumors implanted in mice and caused no overt toxicity despite significant systemic absorption. 2HF treatment reduced phospho-AKT, vimentin, fibronectin, CDK4, cyclinB1, and BCL2, whereas it increased BIM and phospho-AMPK in excised tumors. Several cancer signals are controlled by endocytosis, a process strongly inhibited by RLIP76 depletion. We conclude that 2HF–PLO gel may be useful for topical therapy of cutaneous metastases of melanoma and could enhance the antineoplastic effects of sunitinib and PARP1 inhibitors. The mechanism of action of 2HF in melanoma overlaps with RLI76 inhibitors.

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Section: Discussionsupporting

confidence: 86%

Topical 2′-Hydroxyflavanone for Cutaneous Melanoma

Bose

Singh

Igid

et al. 2019

Cancers

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“…Rlip is a stress-protective, anti-apoptotic mercapturic acid pathway transporter protein in the Ral/Rac/Rho cancer-signaling pathways which also facilitates the efflux of toxic ω-6 fatty acid metabolites and drugs from cells to increase cancer cell survival [26,58,62]. We have previously demonstrated that Rlip depletion prevents or treats chemically induced, xenograft and spontaneous cancers in mouse models and has existential importance for cancer cell formation and survival [26,58,62,79,80]. The functions of the tumor suppressor p53 are lost or altered in a majority of breast cancers.…”

Section: Discussionmentioning

confidence: 99%

Haploinsufficiency Interactions between RALBP1 and p53 in ERBB2 and PyVT Models of Mouse Mammary Carcinogenesis

Singh

Lee

Bose

et al. 2021

Cancers

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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.

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“…Mercapturic acid pathway transporters remove mercapturic acid precursor GSHelectrophile conjugates (GS-E) from cells [33][34][35]. RALBP1 encodes RLIP76 (referred to here as Rlip), a 76 kDa splice variant protein that binds the clathrin-dependent endocytosis (CDE) complex through the clathrin adaptor protein AP2 [36,37]. Rlip possesses ATPase and GS-E transport activities that are coupled with the internalization of peptide hormone/receptor complexes by CDE [36,37], and it is present in intracellular tyrosine kinase signaling complexes that also contain Grb2/Nck and Shc [36,[38][39][40].…”

Section: Introductionmentioning

confidence: 99%

RALBP1 in Oxidative Stress and Mitochondrial Dysfunction in Alzheimer’s Disease

Awasthi

Hindle

Sawant

et al. 2021

Cells

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The purpose of our study is to understand the role of the RALBP1 gene in oxidative stress (OS), mitochondrial dysfunction and cognition in Alzheimer’s disease (AD) pathogenesis. The RALPB1 gene encodes the 76 kDa protein RLIP76 (Rlip). Rlip functions as a stress-responsive/protective transporter of glutathione conjugates (GS-E) and xenobiotic toxins. We hypothesized that Rlip may play an important role in maintaining cognitive function. The aim of this study is to determine whether Rlip deficiency in mice is associated with AD-like cognitive and mitochondrial dysfunction. Brain tissue obtained from cohorts of wildtype (WT) and Rlip+/− mice were analyzed for OS markers, expression of genes that regulate mitochondrial fission/fusion, and synaptic integrity. We also examined mitochondrial ultrastructure in brains obtained from these mice and further analyzed the impact of Rlip deficiency on gene networks of AD, aging, stress response, mitochondrial function, and CREB signaling. Our studies revealed a significant increase in the levels of OS markers and alterations in the expression of genes and proteins involved in mitochondrial biogenesis, dynamics and synapses in brain tissues from these mice. Furthermore, we compared the cognitive function of WT and Rlip+/− mice. Behavioral, basic motor and sensory function tests in Rlip+/− mice revealed cognitive decline, similar to AD. Gene network analysis indicated dysregulation of stress-activated gene expression, mitochondrial function and CREB signaling genes in the Rlip+/− mouse brain. Our results suggest that Rlip deficiency-associated increases in OS and mitochondrial dysfunction could contribute to the development or progression of OS-related AD processes.

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RLIP: An existential requirement for breast carcinogenesis

Cited by 10 publications

References 69 publications

Topical 2′-Hydroxyflavanone for Cutaneous Melanoma

Topical 2′-Hydroxyflavanone for Cutaneous Melanoma

Haploinsufficiency Interactions between RALBP1 and p53 in ERBB2 and PyVT Models of Mouse Mammary Carcinogenesis

RALBP1 in Oxidative Stress and Mitochondrial Dysfunction in Alzheimer’s Disease

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