Induction of mitotic catastrophe by PKC inhibition in <i>Nf1</i>-deficient cells

Zhou, Xiaodong; Kim, Sung Hoon; Shen, Lei; Lee, Hyo‐Jung; Chen, Changyan

doi:10.4161/cc.29297

Cited by 5 publications

(8 citation statements)

References 52 publications

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“…The genetic suppression of Ral A significantly blocked the proliferation and migration of MPNST cells [ 24 ]. Studies demonstrated that Nf1 -deficient cells were very sensitive to PKC inhibitors that elicited apoptosis, perhaps through influencing the proteasomal pathway or activating mitotic checkpoints [ 19 – 21 ]. In our current investigation, we determined that Ral A functioned downstream of hyper-active Ras and responsible for the induction of a persistent mitotic arrest, which led to apoptosis in HMG-treated Nf1 -deficient or knockdown cells.…”

Section: Discussionmentioning

confidence: 99%

“…Ral A knockdown relieved the defective cells from mitotic arrest, but only partially allows the cells to escape from apoptosis. Previously, we showed that Akt played a role in the induction of apoptosis in Nf1 -deficient cells after HMG treatment and the suppression of Akt partially blocked this apoptotic process [ 21 ]. Together, these data indicate that the apoptotic process elicited by PKC inhibition in Nf1 -deficient cells is orchestrated by multiple events, including Ral A (Figure 7 ).…”

Section: Discussionmentioning

confidence: 99%

“…The cells were kept in a −150 0 C freezer after purchasing. The authentications of sNF96.2 and sNF02.2 cells were tested in each study [ 20 , 21 ]. Human specific Nf1 -deficient tumor (ST) cells were generous gift from Dr. D Lowy at NCI in 2007 and authenticated by the upregulation of Ras or ERK1/2 as described previously [ 20 , 21 ].…”

Section: Methodsmentioning

confidence: 99%

“…The link between PKC and Nf1 function was observed [ 18 ]. In particular, Nf1 -defective cells were highly sensitive to PKC inhibitors [ 19 – 21 ]. It was also showed that PKC phosphorylated Ras-like proteins (Rals) and further regulated their subcellular localizations [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

“…In MPNST cells, a high frequency of mitotic index was often detected [ 43 ]. The suppression of PKC triggered a persistently mitotic arrest in Nf1 deficient cells, which led to a mitotic catastrophe [ 20 , 21 ]. In this process, Chk1 was phosphorylated and cyclin B1 expression was upregulated.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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Nf1 mutations or deletions are suggested to underlie the tumor predisposition of NF1 (neurofibromatosis type 1) and few treatments are available for treating NF1 patients with advanced malignant tumors. Aberrant activation of Ras in Nf1-deficient conditions is responsible for the promotion of tumorigenesis in NF1. PKC is proven to be an important factor in supporting the viability of Nf1-defected cells, but the molecular mechanisms are not fully understood. In this study, we demonstrate that the inhibition of protein kinase C (PKC) by 1-O-Hexadecyl-2-O-methyl-rac-glycerol (HMG, a PKC inhibitor) preferentially sensitizes Nf1-defected cells to apoptosis, via triggering a persistent mitotic arrest. In this process, Ral A is activated. Subsequently, Chk1 is phosphorylated and translocated to the nucleus. Silencing Ral A significantly blocks Chk1 nuclear translocation and releases HMG-treated Nf1-deficient cells from mitotic arrest, resulting in the reduction of the magnitude of apoptosis. Thus, our study reveals that PKC is able to maintain the homeostasis or viability of Nf1-defected cells and may serve as a potential target for developing new therapeutic strategies.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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Photodynamic therapy with TMPyP – Porphyrine induces mitotic catastrophe and microtubule disorganization in HeLa and G361 cells, a comprehensive view of the action of the photosensitizer

Cenklová

2017

Journal of Photochemistry and Photobiology B: Biology

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The roles of GTPase-activating proteins in regulated cell death and tumor immunity

Huang

et al. 2021

J Hematol Oncol

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GTPase-activating protein (GAP) is a negative regulator of GTPase protein that is thought to promote the conversion of the active GTPase-GTP form to the GTPase-GDP form. Based on its ability to regulate GTPase proteins and other domains, GAPs are directly or indirectly involved in various cell requirement processes. We reviewed the existing evidence of GAPs regulating regulated cell death (RCD), mainly apoptosis and autophagy, as well as some novel RCDs, with particular attention to their association in diseases, especially cancer. We also considered that GAPs could affect tumor immunity and attempted to link GAPs, RCD and tumor immunity. A deeper understanding of the GAPs for regulating these processes could lead to the discovery of new therapeutic targets to avoid pathologic cell loss or to mediate cancer cell death.

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Induction of mitotic catastrophe by PKC inhibition in Nf1-deficient cells

Cited by 5 publications

References 52 publications

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

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

Photodynamic therapy with TMPyP – Porphyrine induces mitotic catastrophe and microtubule disorganization in HeLa and G361 cells, a comprehensive view of the action of the photosensitizer

The roles of GTPase-activating proteins in regulated cell death and tumor immunity

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