Ral A, via activating the mitotic checkpoint, sensitizes cells lacking a functional<i>Nf1</i>to apoptosis in the absence of protein kinase C

Ganapathy, Suthakar; Fagman, Johan Bourghardt; Shen, Lei; Yu, Tianqi; Zhou, Xiaodong; Dai, Wei; Makriyannis, Alexandros; Chen, Changyan

doi:10.18632/oncotarget.12607

Cited by 5 publications

(8 citation statements)

References 49 publications

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“…S 1 . Among the pathways identified, Ras signaling is activated by PKC or cross-talk with the PKC pathway 18 , 19 , the MAPK pathway acts downstream of the PKC cascade 20 , PI3K/Akt signaling and cell cycle progression are controlled by the PI3K/Akt/mTOR signaling pathway 21 . These findings were comparable to the results of CMAP analysis on potential molecular targets regulated by Tan IIA.…”

Section: Resultsmentioning

confidence: 99%

“…Ras proteins are key regulators of cell growth, differentiation, and survival, and oncogenic activation of Ras is associated with the etiology and progression of cancer 31 . Emerging evidence indicates that PKC suppression sensitizes tumor cells with oncogenically activated Ras to apoptosis 18 , 19 , 32 . Mitogen-activated protein kinase (MAPK) acts downstream of Ras in the Ras/MAPK pathway that plays an important role in tumorigenesis and malignant progression 33 , 34 .…”

Section: Resultsmentioning

confidence: 99%

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The antitumor natural product tanshinone IIA inhibits protein kinase C and acts synergistically with 17-AAG

Zeng

Wang

et al. 2018

Cell Death Dis

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Tanshinone IIA (Tan IIA), the primary bioactive compound derived from the traditional Chinese medicine (TCM) Salvia miltiorrhiza Bunge, has been reported to possess antitumor activity. However, its antitumor mechanisms are not fully understood. To resolve the potential antitumor mechanism(s) of Tan IIA, its gene expression profiles from our database was analyzed by connectivity map (CMAP) and the CMAP-based mechanistic predictions were confirmed/validated in further studies. Specifically, Tan IIA inhibited total protein kinase C (PKC) activity and selectively suppressed the expression of cytosolic and plasma membrane PKC isoforms ζ and ε. The Ras/MAPK pathway that is closely regulated by the PKC signaling is also inhibited by Tan IIA. While Tan IIA did not inhibit heat shock protein 90 (Hsp90), it synergistically enhanced the antitumor efficacy of the Hsp90 inhibitors 17-AAG and ganetespib in human breast cancer MCF-7 cells. In addition, Tan IIA significantly inhibited PI3K/Akt/mTOR signaling, and induced both cell cycle arrest and autophagy. Collectively, these studies provide new insights into the molecular mechanisms responsible for antitumor activity of Tan IIA.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

The antitumor natural product tanshinone IIA inhibits protein kinase C and acts synergistically with 17-AAG

Zeng

Wang

et al. 2018

Cell Death Dis

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“…Taken together, PKC inhibitors including Go6976 are considered effective molecules to inhibit metastasis due to the influence on cell‐to‐cell and cell‐to‐matrix junctions in bladder cancer . PCK inhibitors have also shown to be effective against malignant peripheral nerve sheath tumors in neurofibromatosis type I . In oncogenic stress situations, some apoptotic signaling pathways are activated.…”

Section: Therapeutic Approaches Targeting Ral In Cancer Therapymentioning

confidence: 99%

Ral signaling pathway in health and cancer

et al. 2017

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The Ral (Ras‐Like) signaling pathway plays an important role in the biology of cells. A plethora of effects is regulated by this signaling pathway and its prooncogenic effectors. Our team has demonstrated the overactivation of the RalA signaling pathway in a number of human malignancies including cancers of the liver, ovary, lung, brain, and malignant peripheral nerve sheath tumors. Additionally, we have shown that the activation of RalA in cancer stem cells is higher in comparison with differentiated cancer cells. In this article, we review the role of Ral signaling in health and disease with a focus on the role of this multifunctional protein in the generation of therapies for cancer. An improved understanding of this pathway can lead to development of a novel class of anticancer therapies that functions on the basis of intervention with RalA or its downstream effectors.

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“…APC-mediated cyclin B1 decay allows cells in mitotic phase to enter next cytokinesis [ 26 , 27 ]. A failure of cells to exit from mitosis leads to the occurrence of genetic instability or mitotic catastrophe/death, depending upon cell types, stimuli or circumstances [ 28 - 33 ]. Arsenic compounds are mutagenic, which is through disrupting cell cycle restriction and chromosomal aberrations or deletions [ 17 , 34 ].…”

Section: Introductionmentioning

confidence: 99%

Chronic low dose arsenic exposure preferentially perturbs mitotic phase of the cell cycle

et al. 2018

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Environmental pollution is a big challenge for human survival. Arsenic compounds are well-known biohazard, the exposure of which is closely linked to onsets of various human diseases, particularly cancers. Upon chronically exposing to arsenic compounds, genomic integrity is often disrupted, leading to tumor development. However, the underlying mechanisms by which chronic, low dose arsenic exposure targets genetic stability to initiate carcinogenesis still remain not fully understood. In this study, human lung epithelial BEAS-2B cells and keratinocytes were treated with 0.5 μM of sodium arsenite for one month (designated as BEAS-2B-SA cells or keratinocytes-SA), and its effect on cell cycle responses was analyzed. After being arrested in mitotic phase of the cell cycle by nocodazole treatment, BEAS-2B-SA cells or keratinocytes-SA were delayed to enter next cytokinesis. The lagging exit of the cells from mitosis was accompanied by a sustained Plk1 phosphorylation, which led to a persistent activation of the mitotic regulators BubR1 and Cdc27. As the result, cyclin B1 (clnB1) degradation was attenuated. BEAS-2B-SA cells or keratinocytes-SA also expressed a constitutively active Akt. The cytogenetic analysis showed an increased numbers of aneuploidy in these cells. The suppression of Akt reversed the aberrant expressions of the mitotic regulators, delay of mitotic exit as well as chromosomal aberrations. Our findings suggest that a long-term exposure to low dose sodium arsenite aberrantly retains the catenation of mitosis, which facilitates establishing genetic instability and predisposes the cells to tumorigenesis.

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Ral A, via activating the mitotic checkpoint, sensitizes cells lacking a functionalNf1to apoptosis in the absence of protein kinase C

Cited by 5 publications

References 49 publications

The antitumor natural product tanshinone IIA inhibits protein kinase C and acts synergistically with 17-AAG

The antitumor natural product tanshinone IIA inhibits protein kinase C and acts synergistically with 17-AAG

Ral signaling pathway in health and cancer

Chronic low dose arsenic exposure preferentially perturbs mitotic phase of the cell cycle

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