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01-08-2016 | Original Article

Rho GTPases: RAC1 polymorphisms affected platinum-based chemotherapy toxicity in lung cancer patients

Authors: Ting Zou, Jiye Yin, Wei Zheng, Ling Xiao, Liming Tan, Juan Chen, Ying Wang, Xiangping Li, Chenyue Qian, Jiajia Cui, Wei Zhang, Honghao Zhou, Zhaoqian Liu

Published in: Cancer Chemotherapy and Pharmacology | Issue 2/2016

Abstract

Purpose

Lung cancer is the leading cause of cancer deaths in the world. The toxicity of platinum-based chemotherapy is a main reason limiting its clinical effects. RAC1, as a member of the Rho family of small guanosine triphosphatases (GTPases), was reported to be related to most cancers, such as breast cancer, gastric cancer, testicular germ cell cancer, and lung cancer. Its potential of becoming a drug target in cancer treatment has been investigated in recent years. The aim of this study was to investigate the association between genetic polymorphisms and platinum-based chemotherapy toxicity.

Methods

We enrolled 317 lung cancer patients randomly. Nineteen polymorphisms of HSP genes and Rho family genes were genotyped by Sequenom MassARRAY. The logistic regression was performed by PLINK to compare the relevance of polymorphisms and toxicity outcome.

Results

We found that the polymorphisms of RAC1 rs836554, rs4720672, and rs12536544 were significantly associated with platinum-based chemotherapy toxicity (p = 0.018, p = 0.044, and p = 0.021, respectively).

Conclusions

RAC1 rs836554, rs4720672, and rs12536544 polymorphisms may be novel and useful genetic markers to predict the toxicity induced by platinum-based chemotherapy in lung cancer patients.

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Siegel RL, Miller KD, Jemal A (2015) Cancer statistics, 2015. CA Cancer J Clin 65(1):5–29CrossRefPubMed

Zhang T, Li J, Xia T, Zhang N, Zhang Y, Zhao J (2015) Association between COX-2 polymorphisms and non-small cell lung cancer susceptibility. Int J Clin Exp Pathol 8(3):3168–3173PubMedPubMedCentral

Boolell V, Alamgeer M, Watkins DN, Ganju V (2015) The evolution of therapies in non-small cell lung cancer. Cancers 7(3):1815–1846CrossRefPubMedPubMedCentral

Cortes-Funes H, Martin C, Abratt R, Lund B (1997) Safety profile of gemcitabine, a novel anticancer agent, in non-small cell lung cancer. Anticancer Drugs 8(6):582–587CrossRefPubMed

Han B, Guo Z, Ma Y, Kang S, Wang Y, Wei Q, Wu X (2015) Association of GSTP1 and XRCC1 gene polymorphisms with clinical outcome of advanced non-small cell lung cancer patients with cisplatin-based chemotherapy. Int J Clin Exp Pathol 8(4):4113–4119PubMedPubMedCentral

Xu X, Han L, Duan L, Zhao Y, Yang H, Zhou B, Ma R, Yuan R, Zhou H, Liu Z (2013) Association between eIF3alpha polymorphism and severe toxicity caused by platinum-based chemotherapy in non-small cell lung cancer patients. Br J Clin Pharmacol 75(2):516–523CrossRefPubMed

Chen J, Yin J, Li X, Wang Y, Zheng Y, Qian C, Xiao L, Zou T, Wang Z, Liu J, Zhang W, Zhou H, Liu Z (2014) WISP1 polymorphisms contribute to platinum-based chemotherapy toxicity in lung cancer patients. Int J Mol Sci 15(11):21011–21027CrossRefPubMedPubMedCentral

Chen J, Wu L, Wang Y, Yin J, Li X, Wang Z, Li H, Zou T, Qian C, Li C, Zhang W, Zhou H, Liu Z (2015) Effect of transporter and DNA repair gene polymorphisms to lung cancer chemotherapy toxicity. Tumour Biol 37(2):2275–2284CrossRefPubMed

Aslan JE, McCarty OJ (2013) Rho GTPases in platelet function. J Throm Haemost JTH 11(1):35–46CrossRef

10.

Chi X, Wang S, Huang Y, Stamnes M, Chen JL (2013) Roles of rho GTPases in intracellular transport and cellular transformation. Int J Mol Sci 14(4):7089–7108CrossRefPubMedPubMedCentral

11.

Marinkovic G, Heemskerk N, van Buul JD, de Waard V (2015) The ins and outs of small GTPase Rac1 in the vasculature. J Pharmacol Exp Ther 354(2):91–102CrossRefPubMed

12.

Matos P, Skaug J, Marques B, Beck S, Verissimo F, Gespach C, Boavida MG, Scherer SW, Jordan P (2000) Small GTPase Rac1: structure, localization, and expression of the human gene. Biochem Biophys Res Commun 277(3):741–751CrossRefPubMed

13.

Sundaram S (2015) Rac1 is a novel interactor of drosophila guanine nucleotide exchange factor GEFmeso. Mol Cell Biochem 404(1–2):259–262CrossRefPubMed

14.

Bid HK, Roberts RD, Manchanda PK, Houghton PJ (2013) RAC1: an emerging therapeutic option for targeting cancer angiogenesis and metastasis. Mol Cancer Ther 12(10):1925–1934CrossRefPubMed

15.

Chen QY, Xu LQ, Jiao DM, Yao QH, Wang YY, Hu HZ, Wu YQ, Song J, Yan J, Wu LJ (2011) Silencing of Rac1 modifies lung cancer cell migration, invasion and actin cytoskeleton rearrangements and enhances chemosensitivity to antitumor drugs. Int J Mol Med 28(5):769–776PubMed

16.

Nahleh Z, Tfayli A, Najm A, El Sayed A, Nahle Z (2012) Heat shock proteins in cancer: targeting the ‘chaperones’. Future Med Chem 4(7):927–935CrossRefPubMed

17.

Kaigorodova EV, Bogatyuk MV (2014) Heat shock proteins as prognostic markers of cancer. Curr Cancer Drug Targets 14(8):713–726CrossRefPubMed

18.

Calderwood SK, Gong J (2016) Heat shock proteins promote cancer: it’s a protection racket. Trends Biochem Sci 41(4):311–323. doi:10.1016/j.tibs.2016.01.003 CrossRefPubMed

19.

Sankhala KK, Mita MM, Mita AC, Takimoto CH (2011) Heat shock proteins: a potential anticancer target. Curr Drug Targets 12(14):2001–2008CrossRefPubMed

20.

Shinozuka K, Tang H, Jones RB, Li D, Nieto Y (2015) Impact of polymorphic variations of gemcitabine metabolism, DNA damage repair, and drug-resistance genes on the effect of high-dose chemotherapy for relapsed or refractory lymphoid malignancies. Biol Blood Marrow Transplant 22(5):843–849CrossRefPubMed

21.

Aznar S, Lacal JC (2001) Rho signals to cell growth and apoptosis. Cancer Lett 165(1):1–10CrossRefPubMed

22.

Hodis E, Watson IR, Kryukov GV, Arold ST, Imielinski M, Theurillat JP, Nickerson E, Auclair D, Li L, Place C, Dicara D, Ramos AH, Lawrence MS, Cibulskis K, Sivachenko A, Voet D, Saksena G, Stransky N, Onofrio RC, Winckler W, Ardlie K, Wagle N, Wargo J, Chong K, Morton DL, Stemke-Hale K, Chen G, Noble M, Meyerson M, Ladbury JE, Davies MA, Gershenwald JE, Wagner SN, Hoon DS, Schadendorf D, Lander ES, Gabriel SB, Getz G, Garraway LA, Chin L (2012) A landscape of driver mutations in melanoma. Cell 150(2):251–263CrossRefPubMedPubMedCentral

23.

Krauthammer M, Kong Y, Ha BH, Evans P, Bacchiocchi A, McCusker JP, Cheng E, Davis MJ, Goh G, Choi M, Ariyan S, Narayan D, Dutton-Regester K, Capatana A, Holman EC, Bosenberg M, Sznol M, Kluger HM, Brash DE, Stern DF, Materin MA, Lo RS, Mane S, Ma S, Kidd KK, Hayward NK, Lifton RP, Schlessinger J, Boggon TJ, Halaban R (2012) Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma. Nat Genet 44(9):1006–1014CrossRefPubMedPubMedCentral

24.

Alan JK, Lundquist EA (2013) Mutationally activated Rho GTPases in cancer. Small GTPases 4(3):159–163CrossRefPubMedPubMedCentral

25.

Bourgine J, Garat A, Allorge D, Crunelle-Thibaut A, Lo-Guidice JM, Colombel JF, Broly F, Billaut-Laden I (2011) Evidence for a functional genetic polymorphism of the Rho-GTPase Rac1. Implication in azathioprine response? Pharmacogenet Genomics 21(6):313–324CrossRefPubMed

26.

Szondy K, Rusai K, Szabo AJ, Nagy A, Gal K, Fekete A, Kovats Z, Losonczy G, Lukacsovits J, Muller V (2012) Tumor cell expression of heat shock protein (HSP) 72 is influenced by HSP72 [HSPA1B A(1267)G] polymorphism and predicts survival in small Cell lung cancer (SCLC) patients. Cancer Invest 30(4):317–322CrossRefPubMed

27.

Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81(3):559–575CrossRefPubMedPubMedCentral

28.

Fortin Ensign SP, Mathews IT, Symons MH, Berens ME, Tran NL (2013) Implications of Rho GTPase signaling in glioma cell invasion and tumor progression. Front Oncol 3:241CrossRefPubMedPubMedCentral

29.

Loirand G, Pacaud P (2014) Involvement of Rho GTPases and their regulators in the pathogenesis of hypertension. Small GTPases 5(4):1–10CrossRefPubMed

30.

Barrows D, Schoenfeld SM, Hodakoski C, Silkov A, Honig B, Couvillon A, Shymanets A, Nuernberg B, Asara JM, Parsons R (2015) PAK kinases mediate the phosphorylation of PREX2 to initiate feedback inhibition of Rac1. J Biol Chem 290(48):28915–28931CrossRefPubMed

31.

Lane J, Martin T, Weeks HP, Jiang WG (2014) Structure and role of WASP and WAVE in Rho GTPase signalling in cancer. Cancer Genomics Proteomics 11(3):155–165PubMed

32.

Alvarez DE, Agaisse H (2015) A role for the small GTPase Rac1 in vaccinia actin-based motility. Small GTPases 6(2):119–122CrossRefPubMedPubMedCentral

33.

Rassool FV, Gaymes TJ, Omidvar N, Brady N, Beurlet S, Pla M, Reboul M, Lea N, Chomienne C, Thomas NS, Mufti GJ, Padua RA (2007) Reactive oxygen species, DNA damage, and error-prone repair: a model for genomic instability with progression in myeloid leukemia? Cancer Res 67(18):8762–8771CrossRefPubMed

34.

Sallmyr A, Fan J, Datta K, Kim KT, Grosu D, Shapiro P, Small D, Rassool F (2008) Internal tandem duplication of FLT3 (FLT3/ITD) induces increased ROS production, DNA damage, and misrepair: implications for poor prognosis in AML. Blood 111(6):3173–3182CrossRefPubMed

35.

Ong CC, Gierke S, Pitt C, Sagolla M, Cheng CK, Zhou W, Jubb AM, Strickland L, Schmidt M, Duron SG, Campbell DA, Zheng W, Dehdashti S, Shen M, Yang N, Behnke ML, Huang W, McKew JC, Chernoff J, Forrest WF, Haverty PM, Chin SF, Rakha EA, Green AR, Ellis IO, Caldas C, O’Brien T, Friedman LS, Koeppen H, Rudolph J, Hoeflich KP (2015) Small molecule inhibition of group I p21-activated kinases in breast cancer induces apoptosis and potentiates the activity of microtubule stabilizing agents. Breast Cancer Res BCR 17:59CrossRefPubMed

36.

Jamieson C, Lui C, Brocardo MG, Martino-Echarri E, Henderson BR (2015) Rac1 augments Wnt signaling by stimulating beta-catenin-lymphoid enhancer factor-1 complex assembly independent of beta-catenin nuclear import. J Cell Sci 128(21):3933–3946CrossRefPubMedPubMedCentral

37.

Schnelzer A, Prechtel D, Knaus U, Dehne K, Gerhard M, Graeff H, Harbeck N, Schmitt M, Lengyel E (2000) Rac1 in human breast cancer: overexpression, mutation analysis, and characterization of a new isoform, Rac1b. Oncogene 19(26):3013–3020CrossRefPubMed

38.

Hsu KL, Tsuboi K, Adibekian A, Pugh H, Masuda K, Cravatt BF (2012) DAGLbeta inhibition perturbs a lipid network involved in macrophage inflammatory responses. Nat Chem Biol 8(12):999–1007CrossRefPubMedPubMedCentral

39.

Oudin MJ, Hobbs C, Doherty P (2011) DAGL-dependent endocannabinoid signalling: roles in axonal pathfinding, synaptic plasticity and adult neurogenesis. Eur J Neurosci 34(10):1634–1646CrossRefPubMed

40.

Tapia-Castillo A, Carvajal CA, Campino C, Vecchiola A, Allende F, Solari S, Garcia L, Lavanderos S, Valdivia C, Fuentes C, Lagos CF, Martinez-Aguayo A, Baudrand R, Aglony M, Garcia H, Fardella CE (2014) Polymorphisms in the RAC1 gene are associated with hypertension risk factors in a Chilean pediatric population. Am J Hypertens 27(3):299–307CrossRefPubMed

Title: Rho GTPases: RAC1 polymorphisms affected platinum-based chemotherapy toxicity in lung cancer patients
Authors: Ting Zou
Jiye Yin
Wei Zheng
Ling Xiao
Liming Tan
Juan Chen
Ying Wang
Xiangping Li
Chenyue Qian
Jiajia Cui
Wei Zhang
Honghao Zhou
Zhaoqian Liu
Publication date: 01-08-2016
Publisher: Springer Berlin Heidelberg
Published in: Cancer Chemotherapy and Pharmacology / Issue 2/2016
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-016-3072-0

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