ATM Inhibition Potentiates Death of Androgen Receptor-inactivated Prostate Cancer Cells with Telomere Dysfunction

Reddy, Vidyavathi; Wu, Min; Ciavattone, Nicholas; McKenty, Nathan; Menon, Mani; Barrack, Evelyn R.; Reddy, G. Prem Veer; Kim, Sahn Ho

doi:10.1074/jbc.m115.671404

Cited by 23 publications

(34 citation statements)

References 52 publications

(79 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…193). Mutational studies of the shelterin protein TIN2 showed that deletions in the C-terminal or N-terminal regions of TIN2 triggered cell death in the AR-negative and p53-deficient PPC-1 prostate cancer cell line but not in the AR-positive and p53-positive LNCaP prostate cancer cell line, suggesting that the telomere complex might be different between AR-negative and AR-positive prostate cancer 194 .…”

Section: Clinical Relevancementioning

confidence: 99%

“…Blocking the repair of these telomere DNA lesions with an ATM inhibitor enhanced cell killing by bicalutamide in both LNCaP (androgen-responsive) and CWR 22Rv1 cells (androgen-insensitive). In this setting, ATM inhibition blocked cell cycle checkpoint arrest, preventing the repair of damaged telomeres caused by AR inhibition, and as a result promoted cell death 193 . These studies suggest that combination treatments including an ATM inhibitor that potentiates the effects of existing androgen deprivation therapies are effective via telomere-directed mechanisms and might have clinical utility in both androgen-sensitive and androgen-insensitive prostate cancer.…”

Section: Clinical Relevancementioning

confidence: 99%

See 1 more Smart Citation

Telomeres and telomerase in prostate cancer development and therapy

Graham

Meeker

2017

Nat Rev Urol

View full text Add to dashboard Cite

Aberrations in telomere biology are among the earliest events in prostate cancer tumorigenesis and continue during tumour progression. Substantial telomere shortening occurs in prostate cancer cells and high-grade prostatic intraepithelial neoplasia. Not all mechanisms of telomere shortening are understood, but oxidative stress from local inflammation might accelerate prostatic telomere loss. Critically short telomeres can drive the accumulation of tumour-promoting genomic alterations; however, continued telomere erosion is unsustainable and must be mitigated to ensure cancer cell survival and unlimited replication potential. Prostate cancers predominantly maintain telomeres by activating telomerase, but alternative mechanisms of telomere extension can occur in metastatic disease. Telomerase activity and telomere length assessment might be useful in prostate cancer diagnosis and prognosis. Telomere shortening in normal stromal cells has been associated with prostate cancer, whereas variable telomere lengths in prostate cancer cells and telomere shortening in cancer-associated stromal cells correlated with lethal disease. Single-agent telomerase-targeted treatments for solid cancers were ineffective in clinical trials but have not been investigated in prostate cancer and might be useful in combination with established regimens. Telomere-directed strategies have not been explored as extensively. Telomere deprotection strategies have the advantage of being effective in both telomerase-dependent and telomerase-independent cancers. Disruption of androgen receptor function in prostate cancer cells results in telomere dysfunction, indicating telomeres and telomerase as potential therapeutic targets in prostate cancer.

show abstract

Section: Clinical Relevancementioning

confidence: 99%

Section: Clinical Relevancementioning

confidence: 99%

Telomeres and telomerase in prostate cancer development and therapy

Graham

Meeker

2017

Nat Rev Urol

View full text Add to dashboard Cite

show abstract

“…The best characterized model so far for studying this is the LNCaP. Androgen deprivation of LNCaP cells results in loss of AR function with a compensatory prosurvival activation of mTOR and concomitant implementation of a cell division arrest by activation of the DNA Damage Response (DDR) mediated by ATR‐Chk1 or ATM‐Chk2 . However, it is not well understood what signals the activation of the DDR and ATR (rev.…”

Section: Introductionmentioning

confidence: 99%

“…6 An attractive strategy to prevent this process would be to bypass the cell cycle arrest via inhibition of ATM or ATR, causing the cells to undertake replication with damaged DNA that would cause mitotic catastrophe, a strategy that was in fact implemented in LNCaP treated concomitantly with bicalutamide and ATM inhibition. 4 But a limitation of this approach is how to make the inhibition of ATM or ATR specific to PCa cells.…”

Section: Introductionmentioning

confidence: 99%

Targeting the TLK1/NEK1 DDR axis with Thioridazine suppresses outgrowth of androgen independent prostate tumors

Singh

Jaiswal

Ghosh

et al. 2019

Intl Journal of Cancer

View full text Add to dashboard Cite

Standard therapy for advanced Prostate Cancer (PCa) consists of antiandrogens, which provide respite from disease progression, but ultimately fail resulting in the incurable phase of the disease: mCRPC. Targeting PCa cells before their progression to mCRPC would greatly improve the outcome. Combination therapy targeting the DNA Damage Response (DDR) has been limited by general toxicity, and a goal of clinical trials is how to target the DDR more specifically. We now show that androgen deprivation therapy (ADT) of LNCaP cells results in increased expression of TLK1B, a key kinase upstream of NEK1 and ATR and mediating the DDR that typically results in a temporary cell cycle arrest of androgen responsive PCa cells. Following DNA damage, addition of the TLK specific inhibitor, thioridazine (THD), impairs ATR and Chk1 activation, establishing the existence of a ADT > TLK1 > NEK1 > ATR > Chk1, DDR pathway, while its abrogation leads to apoptosis. Treatment with THD suppressed the outgrowth of androgen‐independent (AI) colonies of LNCaP and TRAMP‐C2 cells cultured with bicalutamide. Moreover, THD significantly inhibited the growth of several PCa cells in vitro (including AI lines). Administration of THD or bicalutamide was not effective at inhibiting long‐term tumor growth of LNCaP xenografts. In contrast, combination therapy remarkably inhibited tumor growth via bypass of the DDR. Moreover, xenografts of LNCaP cells overexpressing a NEK1‐T141A mutant were durably suppressed with bicalutamide. Collectively, these results suggest that targeting the TLK1/NEK1 axis might be a novel therapy for PCa in combination with standard of care (ADT).

show abstract

“…AR antagonists induce telomere DNA damage in AR-positive LNCaP prostate cancer cells, and a DDR that has the features of a bonafide telomere DDR, namely, activation of ATM, as indicated by an increase in phosphorylated ATM (pATM) at telomeres (6–8). Combined treatment with AR antagonist and ATM inhibitor (ATMi) increases the level of replication protein A (RPA, a marker of unrepaired single stranded DNA) at telomeres, indicating that repair of damaged telomere DNA has been blocked.…”

Section: Introductionmentioning

confidence: 99%

Castration-resistant prostate cancer: Androgen receptor inactivation induces telomere DNA damage, and damage response inhibition leads to cell death

Reddy

Iskander

Hwang

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

Telomere stability is important for cell viability, as cells with telomere DNA damage that 24 is not repaired do not survive. We reported previously that androgen receptor (AR) antagonist 25 induces telomere DNA damage in androgen-sensitive LNCaP prostate cancer cells; this triggers 26 a DNA damage response (DDR) at telomeres that includes activation of ATM, and blocking 27 ATM activation prevents telomere DNA repair and leads to cell death. Remarkably, AR 28 antagonist induces telomere DNA damage and triggers ATM activation at telomeres also in 29 22Rv1 castration-resistant prostate cancer (CRPC) cells that are not growth inhibited by AR 30 antagonist. Treatment with AR antagonist enzalutamide (ENZ) or ATM inhibitor (ATMi) by itself 31 had no effect on growth in vitro or in vivo, but combined treatment with ENZ plus ATMi 32 significantly inhibited cell survival in vitro and tumor growth in vivo. By inducing telomere DNA 33 damage and activating a telomere DDR, an opportunity to inhibit DNA repair and promote cell 34 death was created, even in CRPC cells. 22Rv1 cells express both full-length AR and AR splice 35 variant AR-V7, but full-length AR was found to be the predominant form of AR associated with 36 telomeres and required for telomere stability. Although 22Rv1 growth of untreated 22Rv1 cells 37 appears to be driven by AR-V7, it is, ironically, expression of full-length AR that makes them 38 sensitive to growth inhibition by combined treatment with ENZ plus ATMi. Notably, this 39 combined treatment approach to induce telomere DNA damage and inhibit the DDR was 40 effective in inducing cell death also in other CRPC cell lines (LNCaP/AR and C4-2B). Thus, the 41 use of ENZ in combination with a DDR inhibitor, such as ATMi, may be effective in prolonging 42 disease-free survival of patients with AR-positive metastatic CRPC, even those that co-express 43 AR splice variant. 44 45 3 46 Introduction: 47The critical role of the androgen receptor (AR) in prostate cancer cell proliferation and 48 survival is the enduring basis for treating advanced prostate cancer with drugs that block AR 49 function or androgen biosynthesis (1, 2). However, a relentless challenge is the development of 50 resistance to these treatments, referred to as castration-resistant prostate cancer (CRPC) (3). 51Remarkably, CRPC still relies on AR (4, 5), indicating a need to more fully understand the role 52 of AR in cell survival. In this regard, we have discovered a role of AR in prostate cancer cell 53 telomere stability (6, 7). Notably, inactivation of this role of AR creates a DNA damage 54 response (DDR) target, inactivation of which blocks repair and promotes cell death (8). 55Telomeres are the DNA-protein structures that cap the ends of linear chromosomes, 56 which are double-stranded DNA with a single-stranded overhang (9). Telomeres contain many 57 different proteins that play a role in the maintenance of telomere stability; the best characterized 58 are the six proteins (TRF1, TRF2, Rap1, TIN2, POT1 and TPP1) that comprise a complex 5...

show abstract

ATM Inhibition Potentiates Death of Androgen Receptor-inactivated Prostate Cancer Cells with Telomere Dysfunction

Cited by 23 publications

References 52 publications

Telomeres and telomerase in prostate cancer development and therapy

Telomeres and telomerase in prostate cancer development and therapy

Targeting the TLK1/NEK1 DDR axis with Thioridazine suppresses outgrowth of androgen independent prostate tumors

Castration-resistant prostate cancer: Androgen receptor inactivation induces telomere DNA damage, and damage response inhibition leads to cell death

Contact Info

Product

Resources

About