Diverse Antiapoptotic Signaling Pathways Activated by Vasoactive Intestinal Polypeptide, Epidermal Growth Factor, and Phosphatidylinositol 3-Kinase in Prostate Cancer Cells Converge on BAD

Sastry, Konduru S.; Smith, Alexis Nicole; Karpova, Yelena; Datta, Sandeep Robert; Kulik, George

doi:10.1074/jbc.m602928200

Cited by 44 publications

(75 citation statements)

References 62 publications

(58 reference statements)

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“…The cell viability was judged by measuring the luciferase activity in the cell lysates as described. 19,34 The survival of BAD2SA-expressing CSCs was substantially decreased compared with BADwt-CSCs ( Figure 2d). As CSCs expressed elevated levels of antiapoptotic BCL-XL as shown in Figure 1h, and endogenous BAD was still phosphorylated in BAD2SA-CSCs (Figure 2e), we tested whether BH3-mimetic can further sensitize CSCs to BAD2SA-mediated cell death.…”

Section: Resultsmentioning

confidence: 97%

“…[16][17][18] Previously, we showed that phosphorylation at either site is sufficient to protect prostate cancer cells from apoptosis. [19][20][21] We also showed that BAD promotes prostate tumor growth in mouse models. 22 Clinically, while BAD expression was associated with relapse in tamoxifen-treated breast cancer patients, 23,24 phospho-BAD expression was associated with cisplatin resistance and poor overall survival in ovarian cancer.…”

mentioning

confidence: 74%

“…Our efforts in this study define the role of BAD in CSC biology and point to BAD as a possible 'common' therapeutic target, because it modulated the survival of both CSCs and nonCSCs. 19 CSCs, in which BAD is both overexpressed and constitutively phosphorylated, were unable to survive in the absence of BAD phosphorylation. In vivo, BAD phosphorylation was detected in CSCs of 83% of breast cancer biopsies.…”

Section: Discussionmentioning

confidence: 99%

“…22 Clinically, while BAD expression was associated with relapse in tamoxifen-treated breast cancer patients, 23,24 phospho-BAD expression was associated with cisplatin resistance and poor overall survival in ovarian cancer. 25 Our previous findings along with other reports showing the role of BAD in the apoptosis modulation and growth of DC cells 19,22,26 prompted us to explore the potential role of BAD in the biology of CSCs. We started our investigation by assessing the role of BAD in survival and self-renewal of CSCs.…”

mentioning

confidence: 95%

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Targeting proapoptotic protein BAD inhibits survival and self-renewal of cancer stem cells

Sastry

Al-Muftah

et al. 2014

Cell Death Differ

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Emerging evidence suggests that the resistance of cancer stem cells (CSC) to many conventional therapies is one of the major limiting factors of cancer therapy efficacy. Identification of mechanisms responsible for survival and self-renewal of CSC will help design new therapeutic strategies that target and eliminate both differentiated cancer cells and CSC. Here we demonstrated the potential role of proapoptotic protein BAD in the biology of CSC in melanoma, prostate and breast cancers. We enriched CD44 þ /CD24 À cells (CSC) by tumorosphere formation and purified this population by FACS. Both spheres and CSC exhibited increased potential for proliferation, migration, invasion, sphere formation, anchorage-independent growth, as well as upregulation of several stem cell-associated markers. We showed that the phosphorylation of BAD is essential for the survival of CSC. Conversely, ectopic expression of a phosphorylation-deficient mutant BAD induced apoptosis in CSC. This effect was enhanced by treatment with a BH3-mimetic, ABT-737. Both pharmacological agents that inhibit survival kinases and growth factors that are involved in drug resistance delivered their respective cytotoxic and protective effects by modulating the BAD phosphorylation in CSC. Furthermore, the frequency and self-renewal capacity of CSC was significantly reduced by knocking down the BAD expression. Consistent with our in vitro results, significant phosphorylation of BAD was found in CD44 þ CSC of 83% breast tumor specimens. In addition, we also identified a positive correlation between BAD expression and disease stage in prostate cancer, suggesting a role of BAD in tumor advancement. Our studies unveil the role of BAD in the survival and self-renewal of CSC and propose BAD not only as an attractive target for cancer therapy but also as a marker of tumor progression.

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Section: Resultsmentioning

confidence: 97%

mentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 95%

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Targeting proapoptotic protein BAD inhibits survival and self-renewal of cancer stem cells

Sastry

Al-Muftah

et al. 2014

Cell Death Differ

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“…Akt regulates many of the processes associated with metastatic progression and the emergence of AIPC cells, such as diminished apoptotic response [33] and release from the cell cycle control that follows androgen ablation [34]. Akt can dampen the normal apoptotic response by suppressing the activity of numerous pro-apoptotic proteins, including Bad, caspase-9 and the Forkhead family of transcription factors [35][36][37]. In this study, we investigated an EGFRinhibited signalling pathway in p27-transfected PC3 cells.…”

Section: Discussionmentioning

confidence: 99%

Exogenous p27KIP1 expression induces anti-tumour effects and inhibits the EGFR/PI3K/Akt signalling pathway in PC3 cells

Xia¹,

Luo²,

Wang³

2009

Asian J Androl

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Abstractp27 is a cyclin-dependent kinase inhibitor that regulates the progression of cells from G 1 to S phase of the cell cycle. Loss of p27 has been associated with disease progression and with an unfavourable outcome in prostate cancer. In this study, we investigated whether exogenous p27 expression in the human androgen-independent prostate cancer PC3 cell line had any effect on cell growth, and we studied the molecular mechanisms involved. p27 expression was restored in PC3 cells by plasmid delivery. Cell proliferation and apoptosis were assessed in PC3 cells transfected with p27. We also investigated the effects of p27 on the epidermal growth factor receptor (EGFR)/ phosphatidylinositol 3-kinase (PI3K)/Akt signalling pathway in PC3 cells. By restoring p27 expression in PC3 cells, we observed that p27 reduced proliferation and induced arrest in G 0 /G 1 phase. Moreover, p27-transfected PC3 cells underwent apoptosis, as shown by flow cytometric analysis and western blotting analysis of Bcl-2, Bax, Bad, caspase-3 and poly(ADP-ribose)polymerase expression. Furthermore, the p27-induced anti-tumour action correlated with inhibition of the EGFR/PI3K/Akt signalling pathway, as confirmed by western blotting analysis and densitometry of EGFR, PI3K (p85), Akt and p-Akt S473 expression. Our results suggest that exogenous expression of p27 inhibits the proliferation of PC3 cells through induction of G 1 arrest and apoptosis, and this process correlates with inhibition of the EGFR/PI3K/Akt signalling pathway.

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The small GTPase RhoA is crucial for MC3T3‐E1 osteoblastic cell survival

Yoshida

Clark

Stern

2009

J of Cellular Biochemistry

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Prolongation of cell survival through prevention of apoptosis is considered to be a significant factor leading to anabolic responses in bone. The current studies were carried out to determine the role of the small GTPase, RhoA, in osteoblast apoptosis, since RhoA has been found to be critical for cell survival in other tissues. We investigated the effects of inhibitors and activators of RhoA signaling on osteoblast apoptosis. In addition, we assessed the relationship of this pathway to parathyroid hormone (PTH) effects on apoptotic signaling and cell survival. Rho A is activated by geranylgeranylation, which promotes its membrane anchoring. In serum-starved MC3T3-E1 osteoblastic cells, inhibition of geranylgeranylation with geranylgeranyl transferase I inhibitors increased activity of caspase-3, a component step in the apoptosis cascade, and increased cell death. Dominant negative RhoA and Y27632, an inhibitor of the RhoA effector Rho kinase, also increased caspase-3 activity. A geranylgeranyl group donor, geranylgeraniol, antagonized the effect of the geranylgeranyl tranferase I inhibitor GGTI-2166, but could not overcome the effect of the Rho kinase inhibitor. PTH 1-34, a potent antiapoptotic agent, completely antagonized the stimulatory effects of GGTI-2166, dominant negative RhoA, and Y27632, on caspase-3 activity. The results suggest that RhoA signaling is essential for osteoblastic cell survival but that the survival effects of PTH 1-34 are independent of this pathway. Keywordsosteoblast; RhoA; apoptosis; parathyroid hormone Anti-apototic actions are a mechanism through which a number of stimuli have been proposed to increase osteoblastic activity, leading to anabolic responses in bone. These anti-apoptotic factors include parathyroid hormone (PTH) [Jilka, 2007;Jilka et al., 1999;Sowa et al., 2003;Wang et al., 2007], insulin-like growth factor-I [Grey et al., 2003], endothelin [Van Sant et al., 2007], mechanical loading, [Bran et al., 2008;Pavalko et al., 2003;Weyts et al., 2003] and matrix environment [Buxton et al., 2008]. Activation of protein kinase A appears to be a critical component of the anti-apoptotic response to parathyroid hormone [Chen et al., 2007;Swarthout et al., 2002]. However, other signaling pathways could contribute to anti-apoptotic actions. Our previous studies had shown that parathyroid hormone activates the small G protein RhoA in osteoblastic cells [Radeff et al., 2004]. RhoA signaling promotes survival in other tissues, [Gallagher, 2004;Kobayashi et al., 2004;Reuveny et al., 2004;Stepan et al., 2004;Zhu et al., 2008]. RhoA inactivation by statins leads to apoptosis of human osteosarcoma cells [Fromigue et al., 2006]. However, in some tissues RhoA can induce apoptosis [Del Re et al., 2007;Wu , 2006]. In view of these diverse findings, we were interested in determining whether the pathway is important for survival of osteoblastic cells, and whether it plays a role in the effects of PTH to promote osteoblast survival.RhoA signaling can be manipulated with genetic and pharma...

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Diverse Antiapoptotic Signaling Pathways Activated by Vasoactive Intestinal Polypeptide, Epidermal Growth Factor, and Phosphatidylinositol 3-Kinase in Prostate Cancer Cells Converge on BAD

Cited by 44 publications

References 62 publications

Targeting proapoptotic protein BAD inhibits survival and self-renewal of cancer stem cells

Targeting proapoptotic protein BAD inhibits survival and self-renewal of cancer stem cells

Exogenous p27KIP1 expression induces anti-tumour effects and inhibits the EGFR/PI3K/Akt signalling pathway in PC3 cells

The small GTPase RhoA is crucial for MC3T3‐E1 osteoblastic cell survival

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