Cyclin d1 depletion interferes with cancer oxidative balance and sensitizes cancer cells to senescence

Laphanuwat, Phatthamon; Likasitwatanakul, Pornlada; Sittithumcharee, Gunya; Thaphaengphan, Araya; Chomanee, Nussara; Suppramote, Orawan; Ketaroonrut, Nuttavadee; Charngkaew, Komgrid; Lam, Eric W.‐F.; Okada, Seiji; Panich, Uraiwan; Sampattavanich, Somponnat; Jirawatnotai, Siwanon

doi:10.1242/jcs.214726

Cited by 28 publications

(24 citation statements)

References 39 publications

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“…Mice lacking cyclin D1 were also resistant to breast cancers induced by the erbB-2 and ras oncogenes, but were sensitive to breast cancers induced by other oncogenes like c-myc or Wnt-1. Furthermore, knockdown of cyclin D1 induced oxidative imbalance by elevating intracellular ROS levels in cancer cells, which promoted the senescence of cancer cells through a retinoblastoma-independent pro-senescence pathway [138]. These investigations suggest that anti-breast cancer therapy targeting cyclin D1 could be very specific to breast cancers depending on the activated pathways [127].…”

Section: Cyclin Dmentioning

confidence: 88%

Molecular crosstalk between cancer and neurodegenerative diseases

Seo

Park

2019

Cell. Mol. Life Sci.

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The progression of cancers and neurodegenerative disorders is largely defined by a set of molecular determinants that are either complementarily deregulated, or share remarkably overlapping functional pathways. A large number of such molecules have been demonstrated to be involved in the progression of both diseases. In this review, we particularly discuss our current knowledge on p53, cyclin D, cyclin E, cyclin F, Pin1 and protein phosphatase 2A, and their implications in the shared or distinct pathways that lead to cancers or neurodegenerative diseases. In addition, we focus on the interdependent regulation of brain cancers and neurodegeneration, mediated by intercellular communication between tumor and neuronal cells in the brain through the extracellular microenvironment. Finally, we shed light on the therapeutic perspectives for the treatment of both cancer and neurodegenerative disorders. Keywords Age-related diseases • Cell death • Cell survival • Redox system • Glioma • Neurotoxicity Abbreviations Aβ Amyloid-β AD Alzheimer's disease ALS Amyotrophic lateral sclerosis AMPA α-Amino-3-hydroxy-5-methyl-4isoxazolepropionate APC/C Anaphase promoting complex/ cyclosome APP Amyloid precursor protein ATRA All-trans retinoic acid APL Acute promyelocytic leukemia Bax Bcl-2 associated X BH3 Bcl-2 homology 3 Bim Bcl-2-interacting mediator of cell death BimEL Bim-extra long CDK Cyclin-dependent kinase Cellular and Molecular Life Sciences

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Section: Cyclin Dmentioning

confidence: 88%

Molecular crosstalk between cancer and neurodegenerative diseases

Seo

Park

2019

Cell. Mol. Life Sci.

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“…Additionally, Sp (1, 3, or 4) knockdown induced similar cellular responses, such as enhanced cell death, and gene expression changes (increased apoptosis promoters and decreased apoptosis inhibitors) as we observed in GSTP1 knockdown PDAC cells [ 48 ]. Furthermore, we show the reduced expression of principal cell-cycle regulators, cyclin D1 [ 49 ] and CDK4 [ 50 , 51 ]. Based on these results, we propose a mechanism through which GSTP1 alters MAP kinases and NF-κB signaling, averts apoptosis, and promotes cell survival and proliferation ( Figure 5 D).…”

Section: Discussionmentioning

confidence: 99%

Glutathione S-Transferase pi-1 Knockdown Reduces Pancreatic Ductal Adenocarcinoma Growth by Activating Oxidative Stress Response Pathways

Singh

Mohammad

Orr

et al. 2020

Cancers

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Glutathione S-transferase pi-1 (GSTP1) plays an important role in regulating oxidative stress by conjugating glutathione to electrophiles. GSTP1 is overexpressed in breast, colon, lung, and prostate tumors, where it contributes to tumor progression and drug resistance; however, the role of GSTP1 in pancreatic ductal adenocarcinoma (PDAC) is not well understood. Using shRNA, we knocked down GSTP1 expression in three different PDAC cell lines and determined the effect on cell proliferation, cell cycle progression, and reactive oxygen species (ROS) levels. Our results show GSTP1 knockdown reduces PDAC cell growth, prolongs the G0/G1 phase, and elevates ROS in PDAC cells. Furthermore, GSTP1 knockdown results in the increased phosphorylation of c-Jun N-terminal kinase (JNK) and c-Jun and the decreased phosphorylation of extracellular signal-regulated kinase (ERK), p65, the reduced expression of specificity protein 1 (Sp1), and the increased expression of apoptosis-promoting genes. The addition of the antioxidant glutathione restored cell viability and returned protein expression levels to those found in control cells. Collectively, these data support the working hypothesis that the loss of GSTP1 elevates oxidative stress, which alters mitogen-activated protein (MAP) kinases and NF-κB signaling, and induces apoptosis. In support of these in vitro data, nude mice bearing orthotopically implanted GSTP1-knockdown PDAC cells showed an impressive reduction in the size and weight of tumors compared to the controls. Additionally, we observed reduced levels of Ki-67 and increased expression of cleaved caspase-3 in GSTP1-knockdown tumors, suggesting GSTP1 knockdown impedes proliferation and upregulates apoptosis in PDAC cells. Together, these results indicate that GSTP1 plays a significant role in PDAC cell growth and provides support for the pursuit of GSTP1 inhibitors as therapeutic agents for PDAC.

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“…Another primary way that mTOR confers its regulatory effects on cell proliferation is to upregulate expression of the cell cycle regulator cyclin D1 [47]. CCND1, the cyclin D1 encoding gene, is frequently amplified in breast cancer, and depletion of cyclin D1 suppresses breast cancer progression [48,49]. In response to mTOR inhibition, however, cyclin D1 is elevated by everolimus in various types of cancer [21,22].…”

Section: Discussionmentioning

confidence: 99%

Multi-targeted kinase inhibition alleviates mTOR inhibitor resistance in triple-negative breast cancer

McLaughlin

Noord

et al. 2019

Breast Cancer Res Treat

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Purpose Owing to its genetic heterogeneity and acquired resistance, triple-negative breast cancer (TNBC) is not responsive to single-targeted therapy, causing disproportional cancer-related death worldwide. Combined targeted therapy strategies to block interactive oncogenic signaling networks are being explored for effective treatment of the refractory TNBC subtype. Methods A broad kinase inhibitor screen was applied to profile the proliferative responses of TNBC cells, revealing resistance of TNBC cells to inhibition of the mammalian target of rapamycin (mTOR). A systematic drug combination screen was subsequently performed to identify that AEE788, an inhibitor targeting multiple receptor tyrosine kinases (RTKs) EGFR/ HER2 and VEGFR, synergizes with selective mTOR inhibitor rapamycin as well as its analogs (rapalogs) temsirolimus and everolimus to inhibit TNBC cell proliferation. Results The combination treatment with AEE788 and rapalog effectively inhibits phosphorylation of mTOR and 4EBP1, relieves mTOR inhibition-mediated upregulation of cyclin D1, and maintains suppression of AKT and ERK signaling, thereby sensitizing TNBC cells to the rapalogs. siRNA validation of cheminformatics-based predicted AEE788 targets has further revealed the mTOR interactive RPS6K members (RPS6KA3, RPS6KA6, RPS6KB1, and RPS6KL1) as synthetic lethal targets for rapalog combination treatment. Conclusions mTOR signaling is highly activated in TNBC tumors. As single rapalog treatment is insufficient to block mTOR signaling in rapalog-resistant TNBC cells, our results thus provide a potential multi-kinase inhibitor combinatorial strategy to overcome mTOR-targeted therapy resistance in TNBC cells. Keywords Multi-kinase inhibitor • mTOR-targeted therapy • Drug resistance • Triple-negative breast cancer (TNBC) • Polypharmacology Abbreviations BL Basal-like CDK4 Cyclin-dependent kinase 4 CI Combination index EGF Human epidermal growth factor FC Fold change IC50 Half-maximal inhibitory concentration IM Immunomodulatory KI Kinase inhibitor LAR Luminal androgen receptor-like MSL Mesenchymal stem-like mTOR The mammalian target of rapamycin RTK Receptor tyrosine kinase SRB Sulforhodamine B TNBC Triple-negative breast cancer Electronic supplementary material The online version of this article (

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Cyclin d1 depletion interferes with cancer oxidative balance and sensitizes cancer cells to senescence

Cited by 28 publications

References 39 publications

Molecular crosstalk between cancer and neurodegenerative diseases

Molecular crosstalk between cancer and neurodegenerative diseases

Glutathione S-Transferase pi-1 Knockdown Reduces Pancreatic Ductal Adenocarcinoma Growth by Activating Oxidative Stress Response Pathways

Multi-targeted kinase inhibition alleviates mTOR inhibitor resistance in triple-negative breast cancer

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