p14ARF sensitizes human osteosarcoma cells to cisplatin-induced apoptosis in a p53-independent manner

Yuan, Xiang Wei; Zhu, Xiao Feng; Huang, Xiaofeng; Sheng, Pu Yi; He, Ai Shan; Yang, Zi Bo; Deng, Rong; Feng, Gong Kan; Liao, Wei

doi:10.4161/cbt.6.7.4324

Cited by 10 publications

(4 citation statements)

References 41 publications

(55 reference statements)

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“…The knockdown of ANRIL expression impaired cell proliferation, migration and invasion, and induced cell apoptosis in esophageal cancer, gastric cancer, and lung cancer cell lines [13,14] . ANRIL controlled the epigenetic silencing of p14ARF and p16INK4a, which were important regulators of apoptosis induced by cisplatin [15][16][17] . The results also revealed that ANRIL rs1333049 was associated with the incidence of severe gastrointestinal toxicity.…”

Section: Discussionmentioning

confidence: 99%

Association between well-characterized lung cancer lncRNA polymorphisms and platinum-based chemotherapy toxicity in Chinese patients with lung cancer

et al. 2017

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Platinum-based chemotherapy is the standard first-line treatment for most lung cancer patients. However, the toxicity induced by platinum-based chemotherapy greatly impedes its clinical use. Previous studies showed that long non-coding RNAs (lncRNAs) with over 200 nucleotides in length affect drug response and toxicity. In the present study, we investigated the association of well-characterized lung cancer lncRNA polymorphisms with platinum-based chemotherapy toxicity in Chinese patients with lung cancer. A total of 467 lung cancer patients treated with platinum-based chemotherapy for at least two cycles were recruited. We primarily focused on gastrointestinal and hematological toxicities. A total of 14 potentially functional polymorphisms within 8 lncRNAs (HOTTIP, HOTAIT, H19, ANRIL, CCAT2, MALAT1, MEG3, and POLR2E) were genotyped. Unconditional logistical regression analysis was conducted to assess the associations. Gene-gene and gene-environment interactions were identified using the software generalized multifactor dimensionality reduction (GMDR). ANRIL rs1333049 was associated with severe overall toxicity in an additive model (adjusted OR=0.723, 95% CI=0.541-0.965, P=0.028). ANRIL rs1333049 was also associated with severe gastrointestinal toxicity in both the additive (adjusted OR=0.690, 95% CI=0.489-0.974, P=0.035) and dominant (adjusted OR=0.558, 95% CI=0.335-0.931, P=0.025) models. MEG3 rs116907618 was associated with severe gastrointestinal toxicity in an additive model (adjusted OR=1.717, 95% CI=1.007-2.927, P=0.047). GMDR identified the three-factor interaction model of POLR2E rs3787016-HOTTIP rs3807598-chemotherapy regimen as the best predictive model for hematological toxicity. In conclusion, ANRIL and MEG3 genetic polymorphisms are associated with severe platinum toxicity and could be considered as biomarkers for pretreatment evaluation in Chinese patients with lung cancer.

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Section: Discussionmentioning

confidence: 99%

Association between well-characterized lung cancer lncRNA polymorphisms and platinum-based chemotherapy toxicity in Chinese patients with lung cancer

et al. 2017

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“…Collectively, these results demonstrate that MILIP links c-Myc to inactivating p53. This regulation appears independent of p14 ARF as the cell lines used (A549, MCF-7, HCT116, MDA-MB-231, and U2OS) were deficient in p14 ARF expression [37][38][39][40][41][42][43] . Fig.…”

mentioning

confidence: 99%

c-Myc inactivation of p53 through the pan-cancer lncRNA MILIP drives cancer pathogenesis

et al. 2020

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The functions of the proto-oncoprotein c-Myc and the tumor suppressor p53 in controlling cell survival and proliferation are inextricably linked as “Yin and Yang” partners in normal cells to maintain tissue homeostasis: c-Myc induces the expression of ARF tumor suppressor (p14ARF in human and p19ARF in mouse) that binds to and inhibits mouse double minute 2 homolog (MDM2) leading to p53 activation, whereas p53 suppresses c-Myc through a combination of mechanisms involving transcriptional inactivation and microRNA-mediated repression. Nonetheless, the regulatory interactions between c-Myc and p53 are not retained by cancer cells as is evident from the often-imbalanced expression of c-Myc over wildtype p53. Although p53 repression in cancer cells is frequently associated with the loss of ARF, we disclose here an alternate mechanism whereby c-Myc inactivates p53 through the actions of the c-Myc-Inducible Long noncoding RNA Inactivating P53 (MILIP). MILIP functions to promote p53 polyubiquitination and turnover by reducing p53 SUMOylation through suppressing tripartite-motif family-like 2 (TRIML2). MILIP upregulation is observed amongst diverse cancer types and is shown to support cell survival, division and tumourigenicity. Thus our results uncover an inhibitory axis targeting p53 through a pan-cancer expressed RNA accomplice that links c-Myc to suppression of p53.

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“…On its own, p14 ARF did not induce apoptosis, but rather sensitized cells to apoptosis in the presence of camptothecin and adriamycin, inhibitors of topoisomerase I and II, in osteosarcoma, colorectal, melanoma, and fibroblast cell lines [ 121 ]. This effect is also observed in osteosarcoma cell lines in response to cisplatin-induced apoptosis, however, effects were independent of p53 [ 122 ], suggesting a distinct regulatory mechanism that may be treatment dependent.…”

Section: Clinical Implications Of Cdkn2a: Impact On Response and Rmentioning

confidence: 87%

Genetic Alterations in the INK4a/ARF Locus: Effects on Melanoma Development and Progression

2020

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Genetic alterations in the INK4a/ARF (or CDKN2A) locus have been reported in many cancer types, including melanoma; head and neck squamous cell carcinomas; lung, breast, and pancreatic cancers. In melanoma, loss of function CDKN2A alterations have been identified in approximately 50% of primary melanomas, in over 75% of metastatic melanomas, and in the germline of 40% of families with a predisposition to cutaneous melanoma. The CDKN2A locus encodes two critical tumor suppressor proteins, the cyclin-dependent kinase inhibitor p16INK4a and the p53 regulator p14ARF. The majority of CDKN2A alterations in melanoma selectively target p16INK4a or affect the coding sequence of both p16INK4a and p14ARF. There is also a subset of less common somatic and germline INK4a/ARF alterations that affect p14ARF, while not altering the syntenic p16INK4a coding regions. In this review, we describe the frequency and types of somatic alterations affecting the CDKN2A locus in melanoma and germline CDKN2A alterations in familial melanoma, and their functional consequences in melanoma development. We discuss the clinical implications of CDKN2A inactivating alterations and their influence on treatment response and resistance.

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p14ARF sensitizes human osteosarcoma cells to cisplatin-induced apoptosis in a p53-independent manner

Cited by 10 publications

References 41 publications

Association between well-characterized lung cancer lncRNA polymorphisms and platinum-based chemotherapy toxicity in Chinese patients with lung cancer

Association between well-characterized lung cancer lncRNA polymorphisms and platinum-based chemotherapy toxicity in Chinese patients with lung cancer

c-Myc inactivation of p53 through the pan-cancer lncRNA MILIP drives cancer pathogenesis

Genetic Alterations in the INK4a/ARF Locus: Effects on Melanoma Development and Progression

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