Staurosporine-induced G 1 arrest in cancer cells depends on an intact pRB but is independent of p16 status

Zhou, Weibo; Lin, Ying‐Chin; Wersto, Robert P.; Chrest, Joseph; Gabrielson, Edward

doi:10.1016/s0304-3835(02)00101-5

Cited by 5 publications

(6 citation statements)

References 17 publications

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“…The protection observed was in a p53-independent and pRb-dependent manner (2). Other labs have similarly revealed the importance of pRb in the staurosporine-mediated G 1 arrest process (3,(10)(11)(12)(13).…”

Section: Discussionmentioning

confidence: 82%

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The Differential Staurosporine-Mediated G1 Arrest in Normal versus Tumor Cells Is Dependent on the Retinoblastoma Protein

McGahren-Murray¹,

Terry²,

Keyomarsi³

2006

Cancer Research

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Previously, we reported that breast cancer cells with retinoblastoma (pRb) pathway-defective checkpoints can be specifically targeted with chemotherapeutic agents, following staurosporine-mediated reversible growth inhibition in normal cells. Here we set out to determine if the kinetics of staurosporine-mediated growth inhibition is specifically targeted to the G 1 phase of cells, and if such G 1 arrest requires the activity of wild-type pRb. Normal human mammary epithelial and immortalized cells with intact pRb treated with low concentrations of staurosporine arrested in the G 1 phase of the cell cycle, whereas pRb-defective cells showed no response. The duration of G 1 and transition from G 1 to S phase entry were modulated by staurosporine in Rb-intact cells. In pRb + cells, but not in Rb À cells, low concentrations of staurosporine also resulted in a significant decrease in cyclin-dependent kinase 4 (CDK4) expression and activity. To directly assess the role of pRb in staurosporine-mediated G 1 arrest, we subjected wild-type (Rb +/+ ) and pRb À/À mouse embryo fibroblasts (MEFs) to staurosporine treatments. Our results show that whereas Rb +/+ MEFs were particularly sensitive to G 1 arrest mediated by staurosporine, pRb À/À cells were refractory to such treatment. Additionally, CDK4 expression was also inhibited in response to staurosporine only in Rb +/+ MEFs. These results were recapitulated in breast cancer cells treated with siRNA to pRb to down-regulate the pRb expression. Collectively, our data suggest that treatment of cells with nanomolar concentrations of staurosporine resulted in downregulation of CDK4, which ultimately leads to G 1 arrest in normal human mammary epithelial and immortalized cells with an intact pRb pathway, but not in pRb-null/defective cells.

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Section: Discussionmentioning

confidence: 82%

“…Of interest, we found that the protection observed was in a p53-independent and pRb-dependent manner. Other labs have similarly shown that the ability of staurosporine to mediate inhibition of cell proliferation is dependent on an intact pRb pathway (3,(10)(11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

The Differential Staurosporine-Mediated G1 Arrest in Normal versus Tumor Cells Is Dependent on the Retinoblastoma Protein

McGahren-Murray¹,

Terry²,

Keyomarsi³

2006

Cancer Research

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“…In line with our observation, a number of studies have associated the inhibition of CDKs to cell cycle arrest 52 , 53 . Zhou et al reported that treatment of human breast cancer cells with staurosporine causes a reduction in the expression level of CDK that accompanies a G1 cell cycle arrest 54 , while Ishida et al reported that treatment of breast cancer cell lines with herbimycin A caused cell cycle arrest-related reduction of the CDK4 and CDK6 expression levels 55 . In another study, it was reported that treatment of MCF-7 breast cancer cell line with 1,25(OH)2D3 induces cell cycle arrest at G0/G1phase via inhibition of CDK2 and CDK4 56 - 60 .…”

Section: Discussionmentioning

confidence: 99%

BC-N102 suppress breast cancer tumorigenesis by interfering with cell cycle regulatory proteins and hormonal signaling, and induction of time-course arrest of cell cycle at G1/G0 phase

Lawal¹,

Kuo²,

Wu³

et al. 2021

Int. J. Biol. Sci.

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Mechanisms of breast cancer progression and invasion, often involve alteration of hormonal signaling, and upregulation and/or activation of signal transduction pathways that input to cell cycle regulation . Herein, we describe a rationally designed first-in-class novel small molecule inhibitor for targeting oncogenic and hormonal signaling in ER-positive breast cancer. BC-N102 treatment exhibits dose-dependent cytotoxic effects against ER+ breast cancer cell lines. BC-N102 exhibited time course- and dose-dependent cell cycle arrest via downregulation of the estrogen receptor (ER), progesterone receptor (PR), androgen receptor (AR), phosphatidylinositol 3-kinase (PI3K), phosphorylated (p)-extracellular signal-regulated kinase (ERK), p-Akt, CDK2, and CDK4 while increasing p38 mitogen-activated protein kinase (MAPK), and mineralocorticoid receptor (MR) signaling in breast cancer cell line. In addition, we found that BC-N102 suppressed breast cancer tumorigenesis in vivo and prolonged the survival of animals. Our results suggest that the proper application of BC-N102 may be a beneficial chemotherapeutic strategy for ER+ breast cancer patients.

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“…This dephosporylation of Rb in SF-539 cells and our previous findings of Rb dephosphorylation in U251MG cells after staurosporine exposure indicated that Rb could be a target of staurosporine. Indeed, others have also reported that staurosporine cannot cause cells without Rb to accumulate at the G1 phase [9,50] . However, the decrease in phosphorylated Rb after staurosporine exposure did not affect the cycle of Ax-Rbtransfected SF-539 cells under our conditions, probably because the amount of dephosphorylated Rb that originally predominated in the Ax-Rb-transfected SF-539 cells was sufficient to cause G1 arrest.…”

Section: Discussionmentioning

confidence: 99%

“…The results of MTT assays showed that nontransfected and all Ax-mock-transfected cells were simi-larly viable and that the viability of U251MG and D54MG cells transfected with these genes and exposed to staurosporine was not obviously changed (data not shown). However, SF-539 cells transfected with Ax-Rb became resistant to staurosporine after 5 days (IC 50 …”

Section: Rb Expression Status Relative To Staurosporine Sensitivitymentioning

confidence: 99%

Retinoblastoma Protein Prevents Staurosporine-Induced Cell Death in a Retinoblastoma-Defective Human Glioma Cell Line

et al. 2007

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Objective: To investigate the mechanism of staurosporine-induced glioma cell death and cell cycle arrest using adenovirus-mediated gene transfection, as well as the function of retinoblastoma (Rb) and genetic instability induced by staurosporine. Methods: Cell cycle regulation, cell death and nuclear abnormalities induced by staurosporine were examined using an adenovirus vector expressing Rb, p16 or p21 genes in human glioma cell lines. Results: The Rb-defective SF-539 cell line was resistant to staurosporine compared with cell lines expressing intact Rb. SF-539 glioma cells exposed to staurosporine became multinucleated and then died. Multinucleation was prevented in SF-539 cells transfected with the Rb gene, thus decreasing the death rate of these cells. Conclusions: These results imply that enforced Rb expression protects cells from genomic instability induced by staurosporine regardless of its upstream molecular effects.

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Staurosporine-induced G 1 arrest in cancer cells depends on an intact pRB but is independent of p16 status

Cited by 5 publications

References 17 publications

The Differential Staurosporine-Mediated G1 Arrest in Normal versus Tumor Cells Is Dependent on the Retinoblastoma Protein

The Differential Staurosporine-Mediated G1 Arrest in Normal versus Tumor Cells Is Dependent on the Retinoblastoma Protein

BC-N102 suppress breast cancer tumorigenesis by interfering with cell cycle regulatory proteins and hormonal signaling, and induction of time-course arrest of cell cycle at G1/G0 phase

Retinoblastoma Protein Prevents Staurosporine-Induced Cell Death in a Retinoblastoma-Defective Human Glioma Cell Line

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