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

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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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References

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

    Article  PubMed  Google Scholar 

  2. 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):3168–3173

    CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  4. 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):582–587

    Article  CAS  PubMed  Google Scholar 

  5. 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):4113–4119

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 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):516–523

    Article  CAS  PubMed  Google Scholar 

  7. 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):21011–21027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 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):2275–2284

    Article  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  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):7089–7108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):91–102

    Article  CAS  PubMed  Google Scholar 

  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):741–751

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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):1925–1934

    Article  CAS  PubMed  Google Scholar 

  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):769–776

    PubMed  Google Scholar 

  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):927–935

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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):843–849

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  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):251–263

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):1006–1014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  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):313–324

    Article  CAS  PubMed  Google Scholar 

  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):317–322

    Article  CAS  PubMed  Google Scholar 

  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):559–575

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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 3:241

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

  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):28915–28931

    Article  CAS  PubMed  Google Scholar 

  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):155–165

    PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):8762–8771

    Article  CAS  PubMed  Google Scholar 

  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):3173–3182

    Article  CAS  PubMed  Google Scholar 

  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 17:59

    Article  PubMed  Google Scholar 

  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):3933–3946

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):3013–3020

    Article  CAS  PubMed  Google Scholar 

  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):999–1007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):1634–1646

    Article  PubMed  Google Scholar 

  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):299–307

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by the National High-tech R&D Program of China (863 Program) (2012AA02A517), National Natural Science Foundation of China (81373490, 81573508, 81573463), Hunan Provincial Science and Technology Plan of China (2015TP1043), and Open Foundation of Innovative Platform in University of Hunan Province of China (2015-14).

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Authors and Affiliations

  1. Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, People’s Republic of China

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

  2. Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, 410078, People’s Republic of China

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

  3. Hunan Province Cooperation Innovation Center for Molecular Target New Drug Study, Hengyang, 421001, People’s Republic of China

    Jiye Yin, Juan Chen, Wei Zhang, Honghao Zhou & Zhaoqian Liu

  4. The Affiliated Cancer Hospital of XiangYa School of Medicine, Central South University, Changsha, 410014, People’s Republic of China

    Ying Wang

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  1. Ting Zou
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  2. Jiye Yin
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  3. Wei Zheng
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  13. Zhaoqian Liu
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Correspondence to Zhaoqian Liu.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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Zou, T., Yin, J., Zheng, W. et al. Rho GTPases: RAC1 polymorphisms affected platinum-based chemotherapy toxicity in lung cancer patients. Cancer Chemother Pharmacol 78, 249–258 (2016). https://doi.org/10.1007/s00280-016-3072-0

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