FASN regulates cellular response to genotoxic treatments by increasing PARP-1 expression and DNA repair activity via NF-κB and SP1

Wu, Xi; Dong, Zizheng; Wang, Chao J.; Barlow, Lincoln James; Fako, Valerie; Serrano, Moises A.; Zou, Yue; Liu, Jing Yuan; Zhang, Jian-Ting

doi:10.1073/pnas.1609934113

Cited by 69 publications

(81 citation statements)

References 55 publications

(47 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recently, therapies targeting AR have been shown to be effective in SDC patients and have attracted attention [32]. The overexpression of FASN was reported to be linked to castration-resistant prostate cancer growth and resistance to chemotherapy [24,33]. Future studies are expected to clarify the association between these therapies and the FASN expression in SDC.…”

Section: Discussionmentioning

confidence: 99%

The clinicopathological significance of the adipophilin and fatty acid synthase expression in salivary duct carcinoma

et al. 2020

View full text Add to dashboard Cite

Salivary duct carcinoma (SDC) is an aggressive, uncommon tumor histologically comparable to high-grade mammary ductal carcinoma. SDCs are usually androgen receptor (AR)-positive and often HER2-positive. Recently, therapies targeting these molecules for SDC have attracted attention. Lipid metabolism changes have been described in association with biological behavior in various cancers, although no such relationship has yet been reported for SDC. We therefore analyzed the clinicopathological relevance of the immunohistochemical expression of adipophilin (ADP) and fatty acid synthase (FASN), representative lipid metabolism-related proteins, in 147 SDCs. ADP and FASN were variably immunoreactive in most SDCs (both 99.3%), and the ADP and FASN expression was negatively correlated (P = 0.014). ADPpositive (≥ 5%) SDCs more frequently exhibited a prominent nuclear pleomorphism and high-Ki-67 labeling index than those ADP-negative (P = 0.013 and 0.011, respectively). In contrast, a high FASN score, calculated by the staining proportion and intensity, (≥ 120) was correlated with the high expression of AR and FOXA1 (P < 0.001 and = 0.003, respectively). The ADP and FASN expression differed significantly among the subtypes based on biomarker immunoprofiling, as assessed by the AR, HER2, and Ki-67 status (P = 0.017 and 0.003, respectively). A multivariate analysis showed that ADP-positive expression was associated with a shorter overall and progression-free survival (P = 0.018 and 0.003, respectively). ADP was associated with an aggressive histopathology and unfavorable prognosis, and FASN may biologically interact with the AR signaling pathway in SDC. ADP may, therefore, be a new prognostic indicator and therapeutic target in SDC.

show abstract

Section: Discussionmentioning

confidence: 99%

The clinicopathological significance of the adipophilin and fatty acid synthase expression in salivary duct carcinoma

et al. 2020

View full text Add to dashboard Cite

show abstract

“…However, PARP1 may mediate 14-3-3σ regulation of Chk2 expression. Recently, we have shown that the PARP1 gene promoter contains a NF-κB-binding element and that NF-κB negatively regulates PARP1 expression in another cell line, Panc-1 (20). It has also been shown that 14-3-3 proteins could bind to both p65 and IκBα and facilitate the nuclear export of IκBα-p65 complexes (44).…”

Section: Discussionmentioning

confidence: 99%

“…The host cell reactivation-based NHEJ assay was performed as previously described with modifications (20). Briefly, 5×10 4 cells/well were seeded in 24-well plates and cultured for 24 hrs before transfection with either linearized or intact pGL3-Luc plasmid with firefly luciferase reporter gene (400 ng/well) using Metafectene Pro.…”

Section: Methodsmentioning

confidence: 99%

14-3-3σ Contributes to Radioresistance By Regulating DNA Repair and Cell Cycle via PARP1 and CHK2

Chen

Dong

et al. 2017

Molecular Cancer Research

Self Cite

View full text Add to dashboard Cite

14-3-3σ has been implicated in the development of chemo and radiation resistance and in poor prognosis of multiple human cancers. While it has been postulated that 14-3-3σ contributes to these resistances via inhibiting apoptosis and arresting cells in G2/M phase of the cell cycle, the molecular basis of this regulation is currently unknown. In this study, we tested the hypothesis that 14-3-3σ causes resistance to DNA-damaging treatments by enhancing DNA repair in cells arrested in G2/M phase following DNA-damaging treatments. We showed that 14-3-3σ contributed to ionizing radiation (IR) resistance by arresting cancer cells in G2/M phase following IR and by increasing non-homologous end joining (NHEJ) repair of the IR-induced DNA double strand breaks (DSBs). The increased NHEJ repair activity was due to 14-3-3σ-mediated up-regulation of Poly(ADP-ribose) polymerase 1 (PARP1) expression that promoted the recruitment of DNA-PKcs to the DNA damage sites for repair of DSBs. On the other hand, the increased G2/M arrest following IR was due to 14-3-3σ-induced Chk2 expression. Implications These findings reveal an important molecular basis of 14-3-3σ function in cancer cell resistance to chemo/radiation therapy and in poor prognosis of human cancers.

show abstract

“…This observation may have translational implications, since olaparib, rucaparib, and niraparib were recently approved by the FDA as maintenance therapy in platinum-sensitive patients, regard- PARP-1 expression may also play a role in predicting inherent or incurred DNA damage burden to identify DNA repair deficiencies or even treatment response as a functional biomarker of HRD (44,45). We are currently entering several clinical trials in both breast and ovarian cancer at the University of Pennsylvania to directly evaluate [ …”

Section: L I N I C a L M E D I C I N Ementioning

confidence: 99%

A PET imaging agent for evaluating PARP-1 expression in ovarian cancer

Makvandi

Pantel

Schwartz

et al. 2018

Journal of Clinical Investigation

106

107

View full text Add to dashboard Cite

50% of patients with HRD respond to PARPi therapy (3). Moreover, patients without known HRD have also shown a clinical benefit from PARPis, as seen in recent trials assessing niraparib, olaparib, or rucaparib, as maintenance therapy in platinum-sensitive recurrent ovarian cancer (5-8). Given that not all patients will respond to PARPi therapy, improved clinical tools for predicting which patients will respond are urgently needed.Numerous clinical trials have led to FDA approval of 3 PARPis since 2014 and there is continued development of 2 additional drugs within this class (9-13). Despite growth in the BACKGROUND. Poly(ADP-ribose) polymerase (PARP) inhibitors are effective in a broad population of patients with ovarian cancer; however, resistance caused by low enzyme expression of the drug target PARP-1 remains to be clinically evaluated in this context. We hypothesize that PARP-1 expression is variable in ovarian cancer and can be quantified in primary and metastatic disease using a novel PET imaging agent. METHODS.We used a translational approach to describe the significance of PET imaging of PARP-1 in ovarian cancer. First, we produced PARP1-KO ovarian cancer cell lines using CRISPR/Cas9 gene editing to test the loss of PARP-1 as a resistance mechanism to all clinically used PARP inhibitors. Next, we performed preclinical microPET imaging studies using ovarian cancer patient-derived xenografts in mouse models. Finally, in a phase I PET imaging clinical trial we explored PET imaging as a regional marker of PARP-1 expression in primary and metastatic disease through correlative tissue histology. RESULTS.We found that deletion of PARP1 causes resistance to all PARP inhibitors in vitro, and microPET imaging provides proof of concept as an approach to quantify PARP-1 in vivo. Clinically, we observed a spectrum of standard uptake values (SUVs) ranging from 2-12 for PARP-1 in tumors. In addition, we found a positive correlation between PET SUVs and fluorescent immunohistochemistry for PARP-1 (r 2 = 0.60).CONCLUSION. This work confirms the translational potential of a PARP-1 PET imaging agent and supports future clinical trials to test PARP-1 expression as a method to stratify patients for PARP inhibitor therapy.TRIAL REGISTRATION. Clinicaltrials.gov NCT02637934. 22-24). Furthermore, PARP-1 has been development and application of PARPis, the primary drug target poly(ADP-ribose) polymerase 1 (PARP-1) has never been evaluated in vivo, even though loss of expression in vitro is a wellcharacterized resistance mechanism (3,(14)(15)(16)(17)(18)(19). It was first hypothesized that PARPis work primarily through a synthetic lethality pathway where loss of BRCA1 or BRCA2 combined with chemical inhibition of PARP-1 results in cell death (20, 21). However, it was later shown that deletion of PARP1 did not result in BRCA1-restored cells showed no increase in γH2AX compared with DMSO controls. Olaparib-treated OVCAR8 PARP1-KO G1 and G3 cells showed a 1.3 times increase (ANOVA, **P < 0.01 and ***P < 0.001, respectively) in γH2AX...

show abstract

FASN regulates cellular response to genotoxic treatments by increasing PARP-1 expression and DNA repair activity via NF-κB and SP1

Cited by 69 publications

References 55 publications

The clinicopathological significance of the adipophilin and fatty acid synthase expression in salivary duct carcinoma

The clinicopathological significance of the adipophilin and fatty acid synthase expression in salivary duct carcinoma

14-3-3σ Contributes to Radioresistance By Regulating DNA Repair and Cell Cycle via PARP1 and CHK2

A PET imaging agent for evaluating PARP-1 expression in ovarian cancer

Contact Info

Product

Resources

About