ARF Confers a Context-Dependent Response to Chemotherapy in Muscle-Invasive Bladder Cancer

Owczarek, Tomasz B.; Kobayashi, Takashi; Ramirez, Ricardo; Rong, Lijie; Puzio-Kuter, Anna M.; Iyer, Gopa; Teo, Min Yuen; Sánchez-Vega, Francisco; Wang, Jingqiang; Schultz, Nikolaus; Tian, Zheng; Solit, David B.; Al‐Ahmadie, Hikmat; Abate‐Shen, Cory

doi:10.1158/0008-5472.can-16-2621

Cited by 18 publications

(16 citation statements)

References 55 publications

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“…Interestingly, a substantial percentage (35%) of MIBCs, displays mutant TP53 without corresponding alterations of INK4a/ARF locus. In particular, ARF and not p16 appears significantly overexpressed in MIBC, and mainly localized in the nucleolus of patients-derived bladder cancerous cells [147], a feature that correlates with the tendency to develop chemoresistance. Using a mouse model in which the ARF coding region was conditionally ablated in the bladder tissue of Trp53 -/- /Pten -/- mice, the authors showed that Arf wild-type tumors were markedly resistant to treatment with cisplatin compared with the Arf -null counterpart.…”

Section: Arf Has Pro-oncogenic Functionsmentioning

confidence: 99%

Dual Role of the Alternative Reading Frame ARF Protein in Cancer

et al. 2019

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The CDKN2a/ARF locus expresses two partially overlapping transcripts that encode two distinct proteins, namely p14ARF (p19Arf in mouse) and p16INK4a, which present no sequence identity. Initial data obtained in mice showed that both proteins are potent tumor suppressors. In line with a tumor-suppressive role, ARF-deficient mice develop lymphomas, sarcomas, and adenocarcinomas, with a median survival rate of one year of age. In humans, the importance of ARF inactivation in cancer is less clear whereas a more obvious role has been documented for p16INK4a. Indeed, many alterations in human tumors result in the elimination of the entire locus, while the majority of point mutations affect p16INK4a. Nevertheless, specific mutations of p14ARF have been described in different types of human cancers such as colorectal and gastric carcinomas, melanoma and glioblastoma. The activity of the tumor suppressor ARF has been shown to rely on both p53-dependent and independent functions. However, novel data collected in the last years has challenged the traditional and established role of this protein as a tumor suppressor. In particular, tumors retaining ARF expression evolve to metastatic and invasive phenotypes and in humans are associated with a poor prognosis. In this review, the recent evidence and the molecular mechanisms of a novel role played by ARF will be presented and discussed, both in pathological and physiological contexts.

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Section: Arf Has Pro-oncogenic Functionsmentioning

confidence: 99%

Dual Role of the Alternative Reading Frame ARF Protein in Cancer

et al. 2019

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“…All the animal experiments were conducted in compliance with CIEMAT guidelines, and approved by the Animal Welfare Department of the Comunidad de Madrid (Spain; PROEX 088-15, PROEX 183/15). Palbociclib and CDDP concentrations were chosen based on previously published data (14,15). After 15-30 days of treatment, mice were sacrificed and tumors were collected and processed.…”

Section: Tumor Xenografts and Transgenic Mouse Modelmentioning

confidence: 99%

CDK4/6 Inhibitor as a Novel Therapeutic Approach for Advanced Bladder Cancer Independently of RB1 Status

Rubio

Martínez‐Fernández

Segovia

et al. 2019

Clinical Cancer Research

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Purpose: Bladder cancer is a clinical and social problem due to its high incidence and recurrence rates. It frequently appears in elderly patients showing other medical comorbidities that hamper the use of standard chemotherapy. We evaluated the activity of CDK4/6 inhibitor as a new therapy for patients unfit for cisplatin (CDDP).Experimental Design: Bladder cancer cell lines were tested for in vitro sensitivity to CDK4/6 inhibition. A novel metastatic bladder cancer mouse model was developed and used to test its in vivo activity.Results: Cell lines tested were sensitive to CDK4/6 inhibition, independent on RB1 gene status. Transcriptome analyses and knockdown experiments revealed a major role for FOXM1 in this response. CDK4/6 inhibition resulted in reduced FOXM1 phosphorylation in vitro and in vivo and showed synergy with CDDP, allowing a significant tumor regression. FOXM1 exerted important oncogenic roles in bladder cancer.Conclusions: CDK4/6 inhibitors, alone or in combination, are a novel therapeutic strategy for patients with advanced bladder cancer previously classified as unfit for current treatment options. , and PIE 15/00076 and CB/16/00228 (to J.M. Paramio); FEDER cofounded MINECO ISCIII grant PI15/00993 (to M. Santos); FEDER cofounded MINECO grants SAF2013-49147-P and SAF2016-80874-P and Ramon y Cajal contract RYC-2011-09242 (to S. Ruiz); and a grant from Asociaci on Española contra el C ancer Rubio et al.

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“…Cisplatin is a platinum-based compound that exerts a broad spectrum of anti-tumor activities in various cancers via the formation of both inter- and intra- strand DNA adducts 4. However, intrinsic or acquired cisplatin resistance severely attenuates its therapeutic potential 5. The molecular drivers of cisplatin resistance are still largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Hypoxia-elevated circELP3 contributes to bladder cancer progression and cisplatin resistance

Su¹,

Yang²,

Jiang³

et al. 2019

Int. J. Biol. Sci.

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Hypoxia plays a critical role in cancer biology. It induces genomic instability, which in turn helps cancer cells respond adaptively to meet the needs of carcinogenesis, cancer progression and relapse. Circular RNA has not been reported among the variety of downstream factors in this adaptive response. Although a few studies have demonstrated the important role of circular RNAs in driving human bladder cancer progression, their carcinogenic roles are still under investigated. Here, we identified a hypoxia-elevated circular RNA, circELP3, that contributes to bladder cancer progression and cisplatin resistance. Decreasing the level of circELP3 via siRNA clearly reduced the in vitro proliferation and cisplatin resistance of bladder cancer cells and promoted apoptosis. Interfering with circELP3 suppressed tumor xenograft growth in nude mice in vivo. In addition, lower circELP3-expressing bladder cancer cells displayed poorer self-renewal capacity, as demonstrated by lower levels of sphere formation and stem cell marker expression. Furthermore, in human bladder cancer patients, strong correlations between a high circELP3 level and advanced tumor grade and lymph node metastasis were observed. In summary, we provide the first direct evidence that circular RNA participates in the adaptive response to hypoxia and may play a role in the progression and drug resistance of bladder cancer.

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ARF Confers a Context-Dependent Response to Chemotherapy in Muscle-Invasive Bladder Cancer

Cited by 18 publications

References 55 publications

Dual Role of the Alternative Reading Frame ARF Protein in Cancer

Dual Role of the Alternative Reading Frame ARF Protein in Cancer

CDK4/6 Inhibitor as a Novel Therapeutic Approach for Advanced Bladder Cancer Independently of RB1 Status

Hypoxia-elevated circELP3 contributes to bladder cancer progression and cisplatin resistance

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