NF-κB2/p52 Induces Resistance to Enzalutamide in Prostate Cancer: Role of Androgen Receptor and Its Variants

Nadiminty, Nagalakshmi; Tummala, Ramakumar; Liu, Chengfei; Yang, Joy C.; Lou, Wei; Evans, Christopher P.; Gao, Allen C.

doi:10.1158/1535-7163.mct-13-0027

Cited by 162 publications

(154 citation statements)

References 21 publications

(33 reference statements)

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“…This is a critical finding as ARV expression represents a potential mechanism of resistance to ADT in prostate cancer cells, driving the progression to CRPC (Nadiminty et al 2013). In particular, detection of AR-V7 in circulating tumor cells has been associated with resistance to enzalutamide (Antonarakis et al 2014), which is consistent with the resistance of 22Rv1 cells to this AR antagonist.…”

Section: Discussionmentioning

confidence: 62%

Co-targeting AR and HSP90 suppresses prostate cancer cell growth and prevents resistance mechanisms

Centenera¹,

Carter²,

Gillis³

et al. 2015

Endocrine-Related Cancer

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Persistent androgen receptor (AR) signaling in castration resistant prostate cancer (CRPC) underpins the urgent need for therapeutic strategies that better target this pathway. Combining classes of agents that target different components of AR signaling has the potential to delay resistance and improve patient outcomes. Many oncoproteins, including the AR, rely on the molecular chaperone heat shock protein 90 (Hsp90) for functional maturation and stability. In this study, enhanced anti-proliferative activity of the Hsp90 inhibitors 17-allylamino-demethoxygeldanamycin (17-AAG) and AUY922 in androgen-sensitive and CRPC cells was achieved when the agents were used in combination with AR antagonists bicalutamide or enzalutamide. Moreover, significant caspasedependent cell death was achieved using sub-optimal agent doses that individually have no effect. Expression profiling demonstrated regulation of a broadened set of AR target genes with combined 17-AAG and bicalutamide compared with the respective single agent treatments. This enhanced inhibition of AR signaling was accompanied by impaired chromatin binding and nuclear localization of the AR. Importantly, expression of the AR variant AR-V7 that is implicated in resistance to AR antagonists was not induced by combination treatment. Likewise, the heat shock response that is typically elicited with therapeutic doses of Hsp90 inhibitors, and is a potential mediator of resistance to these agents, was significantly reduced by combination treatment. In summary, the co-targeting strategy in this study more effectively inhibits AR signaling than targeting AR or HSP90 alone and prevents induction of key resistance mechanisms in prostate cancer cells. These findings merit further evaluation of this therapeutic strategy to prevent CRPC growth.

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Section: Discussionmentioning

confidence: 62%

Co-targeting AR and HSP90 suppresses prostate cancer cell growth and prevents resistance mechanisms

Centenera¹,

Carter²,

Gillis³

et al. 2015

Endocrine-Related Cancer

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show abstract

“…6A, 6C). Both p65 and p52 can bind to the Bcl-x L promoter, have been implicated in the regulation of its expression, and protect against intrinsic and extrinsic induced cell death (44)(45)(46)(47). Thus, the differential and independent functions of TNFR1 and TNFR2 in DC may converge at the level of Bcl-2/ Bcl-x L , underlining the central role of Bcl-2 family members in DC function (14,29).…”

Section: Discussionmentioning

confidence: 99%

Dendritic Cell Maturation and Survival Are Differentially Regulated by TNFR1 and TNFR2

Maney

Reynolds

Krippner‐Heidenreich

et al. 2014

The Journal of Immunology

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The capacity of dendritic cells (DC) to regulate adaptive immunity is controlled by their maturation state and lifespan. Although TNF is a well-known maturation and survival factor for DC, the role of the two TNF receptors (TNFR), TNFR1 and TNFR2, in mediating these effects is poorly understood. By using unique TNF variants that selectively signal through TNFR1 and/or TNFR2, we demonstrate differential functions of TNFR in human monocyte-derived and blood CD1c+ DC. Activation of TNFR1, but not TNFR2, efficiently induced DC maturation, as defined by enhanced expression of cell surface maturation markers (CD83, CD86 and HLA-DR) as well as enhanced T-cell stimulatory capacity. In contrast, both TNFR1 and TNFR2 significantly protected DC against cell death indicating that innate signals can promote DC survival in the absence of DC maturation. We further show differential activation of NFκB signaling pathways by the TNFR: TNFR1 activated both the p65 and p52 pathways, whereas TNFR2 triggered p52, but not p65 activation. Accordingly, the p65 NFκB pathway only played a role in the pro-survival effect of TNFR1. However, cell death protection through both TNFR was mediated through the Bcl-2/Bcl-xL pathway. Together, our data show that TNFR1-, but not TNFR2-signaling induces DC maturation, whereas DC survival can be mediated independently through both TNFR. These data indicate differential but partly overlapping responses through TNFR1 and TNFR2 in both inflammatory and conventional DC, and demonstrate that DC maturation and DC survival can be regulated through independent signaling pathways.

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“…IL6 has also been reported to activate NF-kB to maintain and expand the CSC population in breast cancer (Korkaya et al 2012) and PCa (Rajasekhar et al 2011). Notably, the overexpression of NFkB in LNCaP cells has been shown to confer resistance to enzalutamide (Nadiminty et al 2013), possibly through the expansion of the CSC population. Hence, targeting the androgen axis modulates CSC plasticity not only through direct transcriptional regulation, such as SOX2 and NANOG, but also by affecting multiple cell types that comprise the tumor microenvironment.…”

Section: /Cd133mentioning

confidence: 99%

Regulation of tumor cell plasticity by the androgen receptor in prostate cancer

Bishop¹,

Davies

Ketola

et al. 2015

Endocrine-Related Cancer

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Prostate cancer (PCa) has become the most common form of cancer in men in the developed world, and it ranks second in cancer-related deaths. Men that succumb to PCa have a disease that is resistant to hormonal therapies that suppress androgen receptor (AR) signaling, which plays a central role in tumor development and progression. Although AR continues to be a clinically relevant therapeutic target in PCa, selection pressures imposed by androgendeprivation therapies promote the emergence of heterogeneous cell populations within tumors that dictate the severity of disease. This cellular plasticity, which is induced by androgen deprivation, is the focus of this review. More specifically, we address the emergence of cancer stem-like cells, epithelial-mesenchymal or myeloid plasticity, and neuroendocrine transdifferentiation as well as evidence that demonstrates how each is regulated by the AR. Importantly, because all of these cell phenotypes are associated with aggressive PCa, we examine novel therapeutic approaches for targeting therapy-induced cellular plasticity as a way of preventing PCa progression.

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NF-κB2/p52 Induces Resistance to Enzalutamide in Prostate Cancer: Role of Androgen Receptor and Its Variants

Cited by 162 publications

References 21 publications

Co-targeting AR and HSP90 suppresses prostate cancer cell growth and prevents resistance mechanisms

Co-targeting AR and HSP90 suppresses prostate cancer cell growth and prevents resistance mechanisms

Dendritic Cell Maturation and Survival Are Differentially Regulated by TNFR1 and TNFR2

Regulation of tumor cell plasticity by the androgen receptor in prostate cancer

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