Abstract
Owing to its poor prognosis, the World Health Organization (WHO) lists lung cancer on top of the list when it comes to growing mortality rates and incidence. Usually, there are two types of lung cancer, small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC), which also includes adenocarcinoma, squamous cell carcinoma and large cell carcinomas. ARF, also known in humans as p14ARF and in the mouse as p19ARF, is a nucleolar protein and a member of INK4, a family of cyclin-independent kinase inhibitors (CKI). These genes are clustered on chromosome number 9p21 within the locus of CDKN2A. NSCLC has reported the role of p14ARF as a potential target. p14ARF has a basic mechanism to inhibit mouse double minute 2 protein that exhibits inhibitory action on p53, a phosphoprotein tumour suppressor, thus playing a role in various tumour-related activities such as growth inhibition, DNA damage, autophagy, apoptosis, cell cycle arrest and others. Extensive cancer research is ongoing and updated reports regarding the role of ARF in lung cancer are available. This article summarizes the available lung cancer ARF data, its molecular mechanisms and its associated signalling pathways. Attempts have been made to show how p14ARF functions in different types of lung cancer providing a thought to look upon ARF as a new target for treating the debilitating condition of lung cancer.
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References
https://www.who.int/news-room/fact-sheets/detail/cancer. Accessed 08 Dec 2019
https://www.wcrf.org/dietandcancer/cancer-trends/worldwide-cancer-data. Accessed 08 Dec 2019
Ferlay J (2010) Cancer incidence and mortality worldwide: IARC. GLOBOCAN 2008
Lemjabbar-Alaoui H, Hassan O, Yang Y-W, Buchanan P (2015) Lung cancer: biology and treatment options. Biochim Biophys Acta 1856:189–210. https://doi.org/10.1016/j.bbcan.2015.08.002
Cancer Facts & Figures 2019. https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2019.html. Accessed 08 Dec 2019
Masters GA, Temin S, Azzoli CG et al (2015) Systemic therapy for stage IV non-small-cell lung cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol Off J Am Soc Clin Oncol 33:3488–3515. https://doi.org/10.1200/JCO.2015.62.1342
Sandler A, Gray R, Perry MC et al (2006) Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355:2542–2550. https://doi.org/10.1056/NEJMoa061884
Scagliotti GV, Parikh P, von Pawel J et al (2008) Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol Off J Am Soc Clin Oncol 26:3543–3551. https://doi.org/10.1200/JCO.2007.15.0375
Hammerschmidt S, Wirtz H (2009) Lung cancer: current diagnosis and treatment. Dtsch Ärztebl Int 106:809–820. https://doi.org/10.3238/arztebl.2009.0809
Fry WA, Menck HR, Winchester DP (1996) The national cancer data base report on lung cancer. Cancer 77:1947–1955. https://doi.org/10.1002/(SICI)1097-0142(19960501)77:9<1947::AID-CNCR27>3.0.CO;2-Z
Johnson BE, Grayson J, Makuch RW et al (1990) Ten-year survival of patients with small-cell lung cancer treated with combination chemotherapy with or without irradiation. J Clin Oncol Off J Am Soc Clin Oncol 8:396–401. https://doi.org/10.1200/JCO.1990.8.3.396
Arbour KC, Riely GJ (2019) Systemic therapy for locally advanced and metastatic non-small cell lung cancer: a review. JAMA 322(8):764–774
Memon H, Patel BM (2019) Immune checkpoint inhibitors in non-small cell lung cancer: a bird’s eye view. Life Sci 233:116713. https://doi.org/10.1016/j.lfs.2019.116713
Qin A, Kalemkerian GP (2016) Cisplatin, etoposide, and irinotecan for relapsed small-cell lung cancer. Transl Cancer Res 5:S1142–S1144. https://doi.org/10.21037/tcr.2016.11.22
Sekine I, Nishiwaki Y, Kakinuma R et al (2003) Phase I/II trial of weekly cisplatin, etoposide, and irinotecan chemotherapy for metastatic lung cancer: JCOG 9507. Br J Cancer 88:808–813. https://doi.org/10.1038/sj.bjc.6600800
Goto K, Sekine I, Nishiwaki Y et al (2004) Multi-institutional phase II trial of irinotecan, cisplatin, and etoposide for sensitive relapsed small-cell lung cancer. Br J Cancer 91:659–665. https://doi.org/10.1038/sj.bjc.6602056
Oun R, Moussa YE, Wheate NJ (2018) The side effects of platinum-based chemotherapy drugs: a review for chemists. Dalton Trans 47:6645–6653. https://doi.org/10.1039/c8dt00838h
Becker A, van Wijk A, Smit EF, Postmus PE (2010) Side-effects of long-term administration of erlotinib in patients with non-small cell lung cancer. J Thorac Oncol 5:1477–1480. https://doi.org/10.1097/JTO.0b013e3181e981d9
Glimelius B (2005) Benefit-risk assessment of irinotecan in advanced colorectal cancer. Drug Saf 28:417–433. https://doi.org/10.2165/00002018-200528050-00005
Cooper WA, Lam DCL, O’Toole SA, Minna JD (2013) Molecular biology of lung cancer. J Thorac Dis 5:S479–S490. https://doi.org/10.3978/j.issn.2072-1439.2013.08.03
Aviel-Ronen S, Blackhall FH, Shepherd FA, Tsao M-S (2006) K-ras mutations in non-small-cell lung carcinoma: a review. Clin Lung Cancer 8:30–38. https://doi.org/10.3816/CLC.2006.n.030
Herbst RS, Heymach JV, Lippman SM (2008) Lung cancer. N Engl J Med 359:1367–1380. https://doi.org/10.1056/NEJMra0802714
Bhadada SV, Goyal BR, Patel MM (2011) Angiogenic targets for potential disorders. Fundam Clin Pharmacol 25:29–47. https://doi.org/10.1111/j.1472-8206.2010.00814.x
Sherr CJ, Roberts JM (1999) CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 13:1501–1512. https://doi.org/10.1101/gad.13.12.1501
Satyanarayana A, Rudolph KL (2004) p16 and ARF: activation of teenage proteins in old age. J Clin Invest 114:1237–1240. https://doi.org/10.1172/JCI200423437
Mao L, Merlo A, Bedi G et al (1995) A novel p16INK4A transcript. Cancer Res 55:2995–2997
Sherr CJ (2006) Divorcing ARF and p53: an unsettled case. Nat Rev Cancer 6:663–673. https://doi.org/10.1038/nrc1954
Weber JD, Taylor LJ, Roussel MF et al (1999) Nucleolar Arf sequesters Mdm2 and activates p53. Nat Cell Biol 1:20–26. https://doi.org/10.1038/8991
Ozenne P, Eymin B, Brambilla E, Gazzeri S (2010) The ARF tumor suppressor: structure, functions and status in cancer. Int J Cancer 127:2239–2247. https://doi.org/10.1002/ijc.25511
Sharpless NE (2005) INK4a/ARF: a multifunctional tumor suppressor locus. Mutat Res 576:22–38. https://doi.org/10.1016/j.mrfmmm.2004.08.021
Rizos H, Darmanian AP, Mann GJ, Kefford RF (2000) Two arginine rich domains in the p14ARF tumour suppressor mediate nucleolar localization. Oncogene 19:2978–2985. https://doi.org/10.1038/sj.onc.1203629
Xirodimas DP, Chisholm J, Desterro JMS et al (2002) P14ARF promotes accumulation of SUMO-1 conjugated (H)Mdm2. FEBS Lett 528:207–211. https://doi.org/10.1016/s0014-5793(02)03310-0
Yarbrough WG, Bessho M, Zanation A et al (2002) Human tumor suppressor ARF impedes S-phase progression independent of p53. Cancer Res 62:1171–1177
Hemmati PG, Gillissen B, von Haefen C et al (2002) Adenovirus-mediated overexpression of p14 ARF induces p53 and Bax-independent apoptosis. Oncogene 21:3149–3161. https://doi.org/10.1038/sj.onc.1205458
Kamijo T, Bodner S, van de Kamp E et al (1999) Tumor spectrum in ARF-deficient mice. Cancer Res 59:2217–2222
Khan SH, Moritsugu J, Wahl GM (2000) Differential requirement for p19ARF in the p53-dependent arrest induced by DNA damage, microtubule disruption, and ribonucleotide depletion. Proc Natl Acad Sci U S A 97:3266–3271. https://doi.org/10.1073/pnas.050560997
de Stanchina E, McCurrach ME, Zindy F et al (1998) E1A signaling to p53 involves the p19ARF tumor suppressor. Genes Dev 12:2434–2442
Abida WM, Gu W (2008) p53-dependent and p53-independent activation of autophagy by ARF. Cancer Res 68:352–357. https://doi.org/10.1158/0008-5472.CAN-07-2069
Reef S, Zalckvar E, Shifman O et al (2006) A short mitochondrial form of p19ARF induces autophagy and caspase-independent cell death. Mol Cell 22:463–475. https://doi.org/10.1016/j.molcel.2006.04.014
Chin L, Pomerantz J, DePinho RA (1998) The INK4a/ARF tumor suppressor: one gene—two products—two pathways. Trends Biochem Sci 23:291–296. https://doi.org/10.1016/S0968-0004(98)01236-5
Hemmati PG, Normand G, Verdoodt B et al (2005) Loss of p21 disrupts p14 ARF-induced G1 cell cycle arrest but augments p14 ARF-induced apoptosis in human carcinoma cells. Oncogene 24:4114–4128. https://doi.org/10.1038/sj.onc.1208579
Hemmati PG, Güner D, Gillissen B et al (2006) Bak functionally complements for loss of Bax during p14ARF-induced mitochondrial apoptosis in human cancer cells. Oncogene 25:6582–6594. https://doi.org/10.1038/sj.onc.1209668
Müer A, Overkamp T, Gillissen B, Richter A, Pretzsch T, Milojkovic A, Dörken B, Daniel PT, Hemmati P (2012) p14ARF-induced apoptosis in p53 protein-deficient cells is mediated by BH3-only protein-independent derepression of Bak protein through down-regulation of Mcl-1 and Bcl-xL proteins. J Biol Chem 287(21):17343–17352. https://doi.org/10.1074/jbc.M111.314898
Eymin B, Leduc C, Coll J-L et al (2003) p14 ARF induces G 2 arrest and apoptosis independently of p53 leading to regression of tumours established in nude mice. Oncogene 22:1822–1835. https://doi.org/10.1038/sj.onc.1206303
Ozenne P, Dayde D, Brambilla E et al (2013) p14(ARF) inhibits the growth of lung adenocarcinoma cells harbouring an EGFR L858R mutation by activating a STAT3-dependent pro-apoptotic signalling pathway. Oncogene 32:1050–1058. https://doi.org/10.1038/onc.2012.107
Dayde D, Guerard M, Perron P et al (2016) Nuclear trafficking of EGFR by Vps34 represses Arf expression to promote lung tumor cell survival. Oncogene 35:3986–3994. https://doi.org/10.1038/onc.2015.480
Ko A, Han SY, Song J (2018) Regulatory network of ARF in cancer development. Mol Cells 41:381–389. https://doi.org/10.14348/molcells.2018.0100
Nicholson SA, Okby NT, Khan MA et al (2001) Alterations of p14ARF, p53, and p73 genes involved in the E2F-1-mediated apoptotic pathways in non-small cell lung carcinoma. Cancer Res 61:5636–5643
Zhang W, Zhu J, Bai J et al (2010) Comparison of the inhibitory effects of three transcriptional variants of CDKN2A in human lung cancer cell line A549. J Exp Clin Cancer Res 29:74. https://doi.org/10.1186/1756-9966-29-74
Gao N, Hu YD, Cao XY et al (2001) The exogenous wild-type p14ARF gene induces growth arrest and promotes radiosensitivity in human lung cancer cell lines. J Cancer Res Clin Oncol 127:359–367. https://doi.org/10.1007/s004320000184
Oh A-Y, Jung YS, Kim J et al (2016) Inhibiting DX2-p14/ARF interaction exerts antitumor effects in lung cancer and delays tumor progression. Cancer Res 76:4791–4804. https://doi.org/10.1158/0008-5472.CAN-15-1025
Saito K, Takigawa N, Ohtani N et al (2013) Antitumor impact of p14ARF on gefitinib-resistant non-small cell lung cancers. Mol Cancer Ther 12:1616–1628. https://doi.org/10.1158/1535-7163.MCT-12-1239
Li J-G, Li L, Zhang S-W (2013) Different expression of p16INK4a and p14ARF in cervical and lung cancers. Eur Rev Med Pharmacol Sci 17:3007–3011
Herzog CR, Soloff EV, McDoniels AL et al (1996) Homozygous codeletion and differential decreased expression of p15INK4b, p16INK4a-alpha and p16INK4a-beta in mouse lung tumor cells. Oncogene. 13(9):1885–1891
Tango Y, Fujiwara T, Itoshima T et al (2002) Adenovirus-mediated p14ARF gene transfer cooperates with Ad5CMV-p53 to induce apoptosis in human cancer cells. Hum Gene Ther 13:1373–1382. https://doi.org/10.1089/104303402760128595
Collado M, Gil J, Efeyan A et al (2005) Tumour biology: senescence in premalignant tumours. Nature 436:642. https://doi.org/10.1038/436642a
Young NP, Jacks T (2010) Tissue-specific p19Arf regulation dictates the response to oncogenic K-ras. Proc Natl Acad Sci U S A 107:10184–10189. https://doi.org/10.1073/pnas.1004796107
Junttila MR, Karnezis A, Garcia D et al (2010) Selective activation of p53-mediated tumour suppression in high-grade tumours. Nature 468:567–571. https://doi.org/10.1038/nature09526
Busch SE, Moser RD, Gurley KE et al (2014) ARF inhibits the growth and malignant progression of non-small-cell lung carcinoma. Oncogene 33:2665–2673. https://doi.org/10.1038/onc.2013.208
Tam AS, Devereux TR, Patel AC et al (2003) Perturbations of the Ink4a/Arf gene locus in aflatoxin B1-induced mouse lung tumors. Carcinogenesis 24:121–132. https://doi.org/10.1093/carcin/24.1.121
Feldser DM, Kostova KK, Winslow MM et al (2010) Stage-specific sensitivity to p53 restoration during lung cancer progression. Nature 468:572–575. https://doi.org/10.1038/nature09535
Kamijo T, Zindy F, Roussel MF et al (1997) Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19 ARF. Cell 91:649–659. https://doi.org/10.1016/S0092-8674(00)80452-3
Gazzeri S, Della Valle V, Chaussade L et al (1998) The human p19ARF protein encoded by the beta transcript of the p16INK4a gene is frequently lost in small cell lung cancer. Cancer Res 58:3926–3931
Mounawar M, Mukeria A, Calvez FL et al (2007) Patterns of EGFR, HER2, TP53, and KRAS mutations of p14arf expression in non-small cell lung cancers in relation to smoking history. Cancer Res 67:5667–5672. https://doi.org/10.1158/0008-5472.CAN-06-4229
Cortot AB, Younes M, Martel-Planche G et al (2014) Mutation of TP53 and alteration of p14arf expression in EGFR- and KRAS-mutated lung adenocarcinomas. Clin Lung Cancer 15:124–130. https://doi.org/10.1016/j.cllc.2013.08.003
Wang F, Li H, Long J, Ye S (2017) Clinicopathological significance of p14ARF expression in lung cancer: a meta-analysis. OncoTargets Ther 10:2491–2499. https://doi.org/10.2147/OTT.S131954
Yang Z-h, Ruan Y-h, Jin K-w et al (2008) The expression of p14ARF in lung cancer. Chin J Ethnomed Ethnopharmacy 07:4–6
Yang T-t, Wu J-f, Li X-j (2008) Relationship between the expression of p14ARF, mtp53 protein and clinical pathological parameters in non-small cell lung cancer. J Xinxiang Med Coll 25:336–339
Maeda T, Hobbs RM, Pandolfi PP (2005) The transcription factor Pokemon: a new key player in cancer pathogenesis. Cancer Res 65:8575–8578. https://doi.org/10.1158/0008-5472.CAN-05-1055
Zhao Z, Wang S, Yu L et al (2008) Expression of transcription factor Pokemon in non-small cell lung cancer and its clinical significance. Chin Med J 121:445–449
Zhao Z-H, Wang S-F, Yu L et al (2008) Overexpression of Pokemon in non-small cell lung cancer and foreshowing tumor biological behavior as well as clinical results. Lung Cancer 62:113–119. https://doi.org/10.1016/j.lungcan.2008.02.014
Zhao ZH, Wang SF, Cong DG et al (2008) Correlation of the expression of pokemon with p14~(ARF) and bcl-2 and their effects on prognosis of non small cell lung cancer. Tumor 28:121–124
Tian K, Lin L, Jia Z et al (2006) Promoter methylation status and protein expression of p14ARF gene in squamous cell carcinoma and adenocarcinoma of the lung. Chin J Lung Cancer 9:40–44. https://doi.org/10.3779/j.issn.1009-3419.2006.01.11
Tian K, Shen Y, Luo Y, Zhang L (2005) Expression of p14~(ARF) gene in non-small cell lung cancer. Med J Qilu 20:389–393
Xue Q, Sano T, Kashiwabara K et al (2002) Aberrant expression of pRb, p16, p14ARF, MDM2, p21 and p53 in stage I adenocarcinomas of the lung – Xue – 2002 – pathology international – Wiley online library. Pathol Int 52:103–109. https://doi.org/10.1046/j.1440-1827.2002.01321.x
Hsu H-S, Wang Y-C, Tseng R-C, Chang J-W, Chen J-T, Shih C-M, Chen C-Y, Wang Y-C (2004) CpG Island methylation is responsible for p14ARF inactivation and inversely correlates with p53 overexpression in resected non-small cell lung Cancer. Clin Cancer Res 10(14):4734–4741. https://doi.org/10.1158/1078-0432.CCR-03-0704
Vonlanthen S, Heighway J, Tschan MP et al (1998) Expression of p16INK4a/p16α and p19ARF/p16β is frequently altered in non-small cell lung cancer and correlates with p53 overexpression. Oncogene 17:2779–2785. https://doi.org/10.1038/sj.onc.1202501
Zöchbauer-Müller S, Fong KM, Virmani AK, Geradts J, Gazdar AF, John D (2001) Minna aberrant promoter methylation of multiple genes in non-small cell lung cancers. Cancer Res 61(1):249–255
Ohtani N, Yamakoshi K, Takahashi A, Hara E (2004) The p16INK4a-RB pathway: molecular link between cellular senescence and tumor suppression. J Med Investig 51:146–153. https://doi.org/10.2152/jmi.51.146
Sanchez-Cespedes M, Reed AL, Buta M et al (1999) Inactivation of the INK4A/ARF locus frequently coexists with TP53 mutations in non-small cell lung cancer. Oncogene 18:5843–5849. https://doi.org/10.1038/sj.onc.1203003
Seike M, Gemma A, Hosoya Y et al (2000) Increase in the frequency of p16INK4 gene inactivation by hypermethylation in lung cancer during the process of metastasis and its relation to the status of p53. Clin Cancer Res 6:4307–4313
Geradts J, Wilentz RE, Roberts H (2001) utImmunohistochemical detection of the alternate INK4a -encoded tumor suppressor protein p14 ARF in archival human cancers and cell lines using commercial antibodies: correlation with p16 INK4a expression. Mod Pathol 14:1162–1168. https://doi.org/10.1038/modpathol.3880452
Zhang Y, Xiong Y, Yarbrough WG (1998) ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell 92:725–734. https://doi.org/10.1016/S0092-8674(00)81401-4
Pomerantz J, Schreiber-Agus N, Liégeois NJ et al (1998) The Ink4a tumor suppressor gene product, p19Arf, interacts with MDM2 and neutralizes MDM2’s inhibition of p53. Cell 92:713–723. https://doi.org/10.1016/S0092-8674(00)81400-2
Gjerset RA (2006) DNA damage, p14ARF, Nucleophosmin (NPM/B23), and cancer. J Mol Histol 37:239–251. https://doi.org/10.1007/s10735-006-9040-y
Korgaonkar C, Hagen J, Tompkins V et al (2005) Nucleophosmin (B23) targets ARF to nucleoli and inhibits its function. Mol Cell Biol 25:1258–1271. https://doi.org/10.1128/MCB.25.4.1258-1271.2005
Kurki S, Peltonen K, Latonen L et al (2004) Nucleolar protein NPM interacts with HDM2 and protects tumor suppressor protein p53 from HDM2-mediated degradation. Cancer Cell 5:465–475. https://doi.org/10.1016/S1535-6108(04)00110-2
Mascaux C, Bex F, Martin B et al The role of NPM, p14arf and MDM2 in precursors of bronchial squamous cell carcinoma | European Respiratory Society. Eur Respir Soc 32. https://doi.org/10.1183/09031936.00008408
Chen Q, Ding J, Gao W (2003) Immunohistochemical analysis of P14ARF protein expression in non-small cell lung cancer: its prognostic significance. Chin J Lung Cancer 6:283–285. https://doi.org/10.3779/j.issn.1009-3419.2003.04.10
Wang Y, Broderick P, Webb E et al (2008) Common 5p15.33 and 6p21.33 variants influence lung cancer risk. Nat Genet 40:1407–1409. https://doi.org/10.1038/ng.273
Broderick P, Wang Y, Vijayakrishnan J et al (2009) Deciphering the impact of common genetic variation on lung cancer risk: a genome-wide association study. Cancer Res 69:6633–6641. https://doi.org/10.1158/0008-5472.CAN-09-0680
Timofeeva MN, Hung RJ, Rafnar T et al (2012) Influence of common genetic variation on lung cancer risk: meta-analysis of 14 900 cases and 29 485 controls. Hum Mol Genet 21:4980–4995. https://doi.org/10.1093/hmg/dds334
Gil J, Peters G (2006) Regulation of the INK4b-ARF-INK4a tumour suppressor locus: all for one or one for all. Nat Rev Mol Cell Biol 7:667–677. https://doi.org/10.1038/nrm1987
Yang X, Yang L, Dai W, Ye B (2016) Role of p14ARF and p15INK4B promoter methylation in patients with lung cancer: a systematic meta-analysis. OncoTargets Ther 9:6977. https://doi.org/10.2147/OTT.S117161
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Vashi, R., Patel, B.M. Roles of ARF tumour suppressor protein in lung cancer: time to hit the nail on the head!. Mol Cell Biochem 476, 1365–1375 (2021). https://doi.org/10.1007/s11010-020-03996-0
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DOI: https://doi.org/10.1007/s11010-020-03996-0