, Volume 21, Issue 11, pp 1203–1213 | Cite as

Pim kinase isoforms: devils defending cancer cells from therapeutic and immune attacks

  • Goodwin G. JineshEmail author
  • Sharada Mokkapati
  • Keyi Zhu
  • Edwin E. Morales


Pim kinases are being implicated in oncogenic process in various human cancers. Pim kinases primarily deal with three broad categories of functions such as tumorigenesis, protecting cells from apoptotic signals and evading immune attacks. Here in this review, we discuss the regulation of Pim kinases and their expression, and how these kinases defend cancer cells from therapeutic and immune attacks with special emphasis on how Pim kinases maintain their own expression during apoptosis and cellular transformation, defend mitochondria during apoptosis, defend cancer cells from immune attack, defend cancer cells from therapeutic attack, choose localization, self-regulation, activation of oncogenic transcription, metabolic regulation and so on. In addition, we also discuss how Pim kinases contribute to tumorigenesis by regulating cellular transformation and glycolysis to reinforce the importance of Pim kinases in cancer and cancer stem cells.


Blebbishields ROS Mitochondria VEGF CXCR4 P-glycoprotein 



The authors sincerely thank UT MD Anderson Cancer Center for literature access.

Compliance with ethical standards

Conflict of interest

The authors declare no conflicts of interest.


  1. 1.
    Cuypers HT, Selten G, Quint W et al (1984) Murine leukemia virus-induced T-cell lymphomagenesis: integration of proviruses in a distinct chromosomal region. Cell 37:141–150PubMedCrossRefGoogle Scholar
  2. 2.
    Vennstrom B, Sheiness D, Zabielski J, Bishop JM (1982) Isolation and characterization of c-myc, a cellular homolog of the oncogene (v-myc) of avian myelocytomatosis virus strain 29. J Virol 42:773–779PubMedPubMedCentralGoogle Scholar
  3. 3.
    Wyke J (1983) Evolution of oncogenes. From c-src to v-src. Nature 304:491–492PubMedCrossRefGoogle Scholar
  4. 4.
    Saurabh K, Scherzer MT, Shah PP et al (2014) The PIM family of oncoproteins: small kinases with huge implications in myeloid leukemogenesis and as therapeutic targets. Oncotarget 5:8503–8514PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Nawijn MC, Alendar A, Berns A (2011) For better or for worse: the role of Pim oncogenes in tumorigenesis. Nat Rev Cancer 11:23–34PubMedCrossRefGoogle Scholar
  6. 6.
    Telerman A, Amson R, Zakut-Houri R, Givol D (1988) Identification of the human pim-1 gene product as a 33-kilodalton cytoplasmic protein with tyrosine kinase activity. Mol Cell Biol 8:1498–1503PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    van Lohuizen M, Verbeek S, Krimpenfort P et al (1989) Predisposition to lymphomagenesis in pim-1 transgenic mice: cooperation with c-myc and N-myc in murine leukemia virus-induced tumors. Cell 56:673–682PubMedCrossRefGoogle Scholar
  8. 8.
    Li J, Hu XF, Loveland BE, Xing PX (2009) Pim-1 expression and monoclonal antibody targeting in human leukemia cell lines. Exp Hematol 37:1284–1294PubMedCrossRefGoogle Scholar
  9. 9.
    Natarajan K, Xie Y, Burcu M, Linn DE, Qiu Y, Baer MR (2013) Pim-1 kinase phosphorylates and stabilizes 130 kDa FLT3 and promotes aberrant STAT5 signaling in acute myeloid leukemia with FLT3 internal tandem duplication. PloS One 8:e74653PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Saris CJ, Domen J, Berns A (1991) The pim-1 oncogene encodes two related protein-serine/threonine kinases by alternative initiation at AUG and CUG. EMBO J 10:655–664PubMedPubMedCentralGoogle Scholar
  11. 11.
    Jinesh GG, Laing NM, Kamat AM (2016) Smac mimetic with TNF-alpha targets Pim-1 isoforms and reactive oxygen species production to abrogate transformation from blebbishields. Biochem J 473:99–107PubMedCrossRefGoogle Scholar
  12. 12.
    Xie Y, Xu K, Dai B et al (2006) The 44 kDa Pim-1 kinase directly interacts with tyrosine kinase Etk/BMX and protects human prostate cancer cells from apoptosis induced by chemotherapeutic drugs. Oncogene 25:70–78PubMedGoogle Scholar
  13. 13.
    Hu XF, Li J, Vandervalk S, Wang Z, Magnuson NS, Xing PX (2009) PIM-1-specific mAb suppresses human and mouse tumor growth by decreasing PIM-1 levels, reducing Akt phosphorylation, and activating apoptosis. J Clin Invest 119:362–375PubMedPubMedCentralGoogle Scholar
  14. 14.
    Guo S, Mao X, Chen J et al (2010) Overexpression of Pim-1 in bladder cancer. J Exp Clin Cancer Res 29:161PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Levy D, Davidovich A, Zirkin S et al (2012) Activation of cell cycle arrest and apoptosis by the proto-oncogene Pim-2. PloS One 7:e34736PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Park C, Min S, Park EM et al (2015) Pim kinase interacts with nonstructural 5 A protein and regulates hepatitis C virus entry. J Virol 89:10073–10086PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Duverger A, Wolschendorf F, Anderson JC et al (2014) Kinase control of latent HIV-1 infection: PIM-1 kinase as a major contributor to HIV-1 reactivation. J Virol 88:364–376PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Warfel NA, Kraft AS. (2015) PIM kinase (and Akt) biology and signaling in tumors. Pharmacol Ther 151:41–49.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Ionov Y, Le X, Tunquist BJ et al (2003) Pim-1 protein kinase is nuclear in Burkitt’s lymphoma: nuclear localization is necessary for its biologic effects. Anticancer Res 23:167–178PubMedGoogle Scholar
  20. 20.
    Nieborowska-Skorska M, Hoser G, Kossev P, Wasik MA, Skorski T (2002) Complementary functions of the antiapoptotic protein A1 and serine/threonine kinase pim-1 in the BCR/ABL-mediated leukemogenesis. Blood 99:4531–4539PubMedCrossRefGoogle Scholar
  21. 21.
    Herzog S, Fink MA, Weitmann K et al (2015) Pim1 kinase is upregulated in glioblastoma multiforme and mediates tumor cell survival. Neurooncol 17:223–242Google Scholar
  22. 22.
    Pang W, Tian X, Bai F et al (2014) Pim-1 kinase is a target of miR-486-5p and eukaryotic translation initiation factor 4E, and plays a critical role in lung cancer. Mol Cancer 13:240PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Rhodes DR, Sanda MG, Otte AP, Chinnaiyan AM, Rubin MA (2003) Multiplex biomarker approach for determining risk of prostate-specific antigen-defined recurrence of prostate cancer. J Natl Cancer Inst 95:661–668PubMedCrossRefGoogle Scholar
  24. 24.
    Warnecke-Eberz U, Bollschweiler E, Drebber U et al (2009) Prognostic impact of protein overexpression of the proto-oncogene PIM-1 in gastric cancer. Anticancer Res 29:4451–4455PubMedGoogle Scholar
  25. 25.
    Peltola K, Hollmen M, Maula SM et al (2009) Pim-1 kinase expression predicts radiation response in squamocellular carcinoma of head and neck and is under the control of epidermal growth factor receptor. Neoplasia 11:629–636PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Xu D, Allsop SA, Witherspoon SM et al (2011) The oncogenic kinase Pim-1 is modulated by K-Ras signaling and mediates transformed growth and radioresistance in human pancreatic ductal adenocarcinoma cells. Carcinogenesis 32:488–495PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Hu Y, Lu W, Chen G et al (2012) K-ras(G12V) transformation leads to mitochondrial dysfunction and a metabolic switch from oxidative phosphorylation to glycolysis. Cell Res 22:399–412PubMedCrossRefGoogle Scholar
  28. 28.
    Jinesh GG, Jennifer RM, Li H, et al. (2016) Mitochondrial oligomers boost glycolysis in cancer stem cells to facilitate blebbishield-mediated transformation after apoptosis. Cell Death Discov 2:16003PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Aho TL, Sandholm J, Peltola KJ, Mankonen HP, Lilly M, Koskinen PJ. (2004) Pim-1 kinase promotes inactivation of the pro-apoptotic Bad protein by phosphorylating it on the Ser112 gatekeeper site. FEBS Lett 571:43–49PubMedCrossRefGoogle Scholar
  30. 30.
    Fang X, Yu S, Eder A et al (1999) Regulation of BAD phosphorylation at serine 112 by the Ras-mitogen-activated protein kinase pathway. Oncogene 18:6635–6640PubMedCrossRefGoogle Scholar
  31. 31.
    Jinesh GG, Kamat AM (2016) Blebbishield emergency program: an apoptotic route to cellular transformation. Cell Death Differ 23:757–758PubMedCrossRefGoogle Scholar
  32. 32.
    Chan CH, Li CF, Yang WL et al (2012) The Skp2-SCF E3 ligase regulates Akt ubiquitination, glycolysis, herceptin sensitivity, and tumorigenesis. Cell 149:1098–1111PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Yan B, Zemskova M, Holder S et al (2003) The PIM-2 kinase phosphorylates BAD on serine 112 and reverses BAD-induced cell death. J Biol Chem 278:45358–45367PubMedCrossRefGoogle Scholar
  34. 34.
    Deneen B, Welford SM, Ho T, Hernandez F, Kurland I, Denny CT (2003) PIM3 proto-oncogene kinase is a common transcriptional target of divergent EWS/ETS oncoproteins. Mol Cell Biol 23:3897–3908PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Cen B, Mahajan S, Zemskova M et al (2010) Regulation of Skp2 levels by the Pim-1 protein kinase. J Biol Chem 285:29128–29137PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Yokoi S, Yasui K, Iizasa T, Takahashi T, Fujisawa T, Inazawa J (2003) Down-regulation of SKP2 induces apoptosis in lung-cancer cells. Cancer Sci 94:344–349PubMedCrossRefGoogle Scholar
  37. 37.
    Wei Z, Jiang X, Liu F et al (2013) Downregulation of Skp2 inhibits the growth and metastasis of gastric cancer cells in vitro and in vivo. Tumour Biol 34:181–192PubMedCrossRefGoogle Scholar
  38. 38.
    Zhang Y, Wang Z, Magnuson NS (2007) Pim-1 kinase-dependent phosphorylation of p21Cip1/WAF1 regulates its stability and cellular localization in H1299 cells. Mol Cancer Res 5:909–922PubMedCrossRefGoogle Scholar
  39. 39.
    Wang Z, Bhattacharya N, Mixter PF, Wei W, Sedivy J, Magnuson NS (2002) Phosphorylation of the cell cycle inhibitor p21Cip1/WAF1 by Pim-1 kinase. Biochim Biophys Acta 1593:45–55PubMedCrossRefGoogle Scholar
  40. 40.
    Asada M, Yamada T, Ichijo H et al (1999) Apoptosis inhibitory activity of cytoplasmic p21(Cip1/WAF1) in monocytic differentiation. EMBO J 18:1223–1234PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Kawata S, Ariumi Y, Shimotohno K (2003) p21(Waf1/Cip1/Sdi1) prevents apoptosis as well as stimulates growth in cells transformed or immortalized by human T-cell leukemia virus type 1-encoded tax. J Virol 77:7291–7299PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Grundler R, Brault L, Gasser C et al (2009) Dissection of PIM serine/threonine kinases in FLT3-ITD-induced leukemogenesis reveals PIM1 as regulator of CXCL12-CXCR4-mediated homing and migration. J Exp Med 206:1957–1970PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Decker S, Finter J, Forde AJ et al (2014) PIM kinases are essential for chronic lymphocytic leukemia cell survival (PIM2/3) and CXCR4-mediated microenvironmental interactions (PIM1). Mol Cancer Ther 13:1231–1245PubMedCrossRefGoogle Scholar
  44. 44.
    Timofeeva OA, Tarasova NI, Zhang X et al (2013) STAT3 suppresses transcription of proapoptotic genes in cancer cells with the involvement of its N-terminal domain. Proc Natl Acad Sci USA 110:1267–1272PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Huang G, Yan H, Ye S, Tong C, Ying QL (2014) STAT3 phosphorylation at tyrosine 705 and serine 727 differentially regulates mouse ESC fates. Stem Cells 32:1149–1160PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Cen B, Xiong Y, Song JH et al (2014) The Pim-1 protein kinase is an important regulator of MET receptor tyrosine kinase levels and signaling. Mol Cell Biol 34:2517–2532PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Shahbazian D, Parsyan A, Petroulakis E et al (2010) Control of cell survival and proliferation by mammalian eukaryotic initiation factor 4B. Mol Cell Biol 30:1478–1485PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Chen JL, Limnander A, Rothman PB (2008) Pim-1 and Pim-2 kinases are required for efficient pre-B-cell transformation by v-Abl oncogene. Blood 111:1677–1685PubMedCrossRefGoogle Scholar
  49. 49.
    Aho TL, Sandholm J, Peltola KJ, Ito Y, Koskinen PJ (2006) Pim-1 kinase phosphorylates RUNX family transcription factors and enhances their activity. BMC Cell Biol 7:21PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Yamamura Y, Lee WL, Inoue K, Ida H, Ito Y (2006) RUNX3 cooperates with FoxO3a to induce apoptosis in gastric cancer cells. J Biol Chem 281:5267–5276PubMedCrossRefGoogle Scholar
  51. 51.
    Lee CW, Chuang LS, Kimura S et al (2011) RUNX3 functions as an oncogene in ovarian cancer. Gynecol Oncol 122:410–417PubMedCrossRefGoogle Scholar
  52. 52.
    Gu JJ, Wang Z, Reeves R, Magnuson NS (2009) PIM1 phosphorylates and negatively regulates ASK1-mediated apoptosis. Oncogene 28:4261–4271PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Mo JS, Yoon JH, Ann EJ et al (2013) Notch1 modulates oxidative stress induced cell death through suppression of apoptosis signal-regulating kinase 1. Proc Natl Acad Sci USA 110:6865–6870PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Xie Y, Xu K, Linn DE et al (2008) The 44-kDa Pim-1 kinase phosphorylates BCRP/ABCG2 and thereby promotes its multimerization and drug-resistant activity in human prostate cancer cells. J Biol Chem 283:3349–3356PubMedCrossRefGoogle Scholar
  55. 55.
    Deng G, Nagai Y, Xiao Y et al (2015) Pim-2 kinase influences regulatory T cell function and stability by mediating Foxp3 protein N-terminal phosphorylation. J Biol Chem 290:20211–20220PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Tan B, Anaka M, Deb S et al (2014) FOXP3 over-expression inhibits melanoma tumorigenesis via effects on proliferation and apoptosis. Oncotarget 5:264–276PubMedCrossRefGoogle Scholar
  57. 57.
    Wang J, Lao L, Zhao H, Huang Y (2014) Serine threonine kinase Pim-3 regulates STAT3 pathway to inhibit proliferation of human liver cancers. Int J Clin Exp Med 7:348–355PubMedPubMedCentralGoogle Scholar
  58. 58.
    Popivanova BK, Li YY, Zheng H et al (2007) Proto-oncogene, Pim-3 with serine/threonine kinase activity, is aberrantly expressed in human colon cancer cells and can prevent Bad-mediated apoptosis. Cancer Sci 98:321–328PubMedCrossRefGoogle Scholar
  59. 59.
    Roh M, Gary B, Song C et al (2003) Overexpression of the oncogenic kinase Pim-1 leads to genomic instability. Cancer Res 63:8079–8084PubMedGoogle Scholar
  60. 60.
    Frescas D, Pagano M (2008) Deregulated proteolysis by the F-box proteins SKP2 and beta-TrCP: tipping the scales of cancer. Nat Rev Cancer 8:438–449PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Henis-Korenblit S, Strumpf NL, Goldstaub D, Kimchi A (2000) A novel form of DAP5 protein accumulates in apoptotic cells as a result of caspase cleavage and internal ribosome entry site-mediated translation. Mol Cell Biol 20:496–506PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Weingarten-Gabbay S, Khan D, Liberman N et al (2014) The translation initiation factor DAP5 promotes IRES-driven translation of p53 mRNA. Oncogene 33:611–618PubMedCrossRefGoogle Scholar
  63. 63.
    Mahoney DJ, Cheung HH, Mrad RL et al (2008) Both cIAP1 and cIAP2 regulate TNFalpha-mediated NF-kappaB activation. Proc Natl Acad Sci USA 105:11778–11783PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Bratton SB, Lewis J, Butterworth M, Duckett CS, Cohen GM (2002) XIAP inhibition of caspase-3 preserves its association with the Apaf-1 apoptosome and prevents CD95- and Bax-induced apoptosis. Cell Death Differ 9:881–892PubMedCrossRefGoogle Scholar
  65. 65.
    Spriggs KA, Bushell M, Mitchell SA, Willis AE (2005) Internal ribosome entry segment-mediated translation during apoptosis: the role of IRES-trans-acting factors. Cell Death Differ 12:585–591PubMedCrossRefGoogle Scholar
  66. 66.
    Borillo GA, Mason M, Quijada P et al (2010) Pim-1 kinase protects mitochondrial integrity in cardiomyocytes. Circ Res 106:1265–1274PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Zirkin S, Davidovich A, Don J (2013) The PIM-2 kinase is an essential component of the ultraviolet damage response that acts upstream to E2F-1 and ATM. J Biol Chem 288:21770–21783PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Johannes G, Carter MS, Eisen MB, Brown PO, Sarnow P (1999) Identification of eukaryotic mRNAs that are translated at reduced cap binding complex eIF4F concentrations using a cDNA microarray. Proc Natl Acad Sci USA 96:13118–13123PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Beharry Z, Mahajan S, Zemskova M et al (2011) The Pim protein kinases regulate energy metabolism and cell growth. Proc Natl Acad Sci USA 108:528–533PubMedCrossRefGoogle Scholar
  70. 70.
    Nanbru C, Lafon I, Audigier S et al (1997) Alternative translation of the proto-oncogene c-myc by an internal ribosome entry site. J Biol Chem 272:32061–32066PubMedCrossRefGoogle Scholar
  71. 71.
    Yip-Schneider MT, Horie M, Broxmeyer HE (1995) Transcriptional induction of pim-1 protein kinase gene expression by interferon gamma and posttranscriptional effects on costimulation with steel factor. Blood 85:3494–3502PubMedGoogle Scholar
  72. 72.
    Zhu N, Ramirez LM, Lee RL, Magnuson NS, Bishop GA, Gold MR (2002) CD40 signaling in B cells regulates the expression of the Pim-1 kinase via the NF-kappa B pathway. J Immunol 168:744–754PubMedCrossRefGoogle Scholar
  73. 73.
    Anto RJ, Maliekal TT, Karunagaran D (2000) L-929 cells harboring ectopically expressed RelA resist curcumin-induced apoptosis. J Biol Chem 275:15601–15604PubMedCrossRefGoogle Scholar
  74. 74.
    Yang H, Wang Y, Qian H, Zhang P, Huang C (2011) Pim protein kinase-3 is regulated by TNF-alpha and promotes endothelial cell sprouting. Mol Cells 32:235–241PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Block KM, Hanke NT, Maine EA, Baker AF (2012) IL-6 stimulates STAT3 and Pim-1 kinase in pancreatic cancer cell lines. Pancreas 41:773–781PubMedPubMedCentralGoogle Scholar
  76. 76.
    Willert M, Augstein A, Poitz DM, Schmeisser A, Strasser RH, Braun-Dullaeus RC (2010) Transcriptional regulation of Pim-1 kinase in vascular smooth muscle cells and its role for proliferation. Basic Res Cardiol 105:267–277PubMedCrossRefGoogle Scholar
  77. 77.
    Weirauch U, Beckmann N, Thomas M et al (2013) Functional role and therapeutic potential of the pim-1 kinase in colon carcinoma. Neoplasia 15:783–794PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Chen J, Kobayashi M, Darmanin S et al (2009) Pim-1 plays a pivotal role in hypoxia-induced chemoresistance. Oncogene 28:2581–2592PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Fox CJ, Hammerman PS, Cinalli RM, Master SR, Chodosh LA, Thompson CB. (2003) The serine/threonine kinase Pim-2 is a transcriptionally regulated apoptotic inhibitor. Gene Dev 17:1841–1854PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Adam K, Lambert M, Lestang E et al. (2015) Control of Pim2 kinase stability and expression in transformed human hematopoietic cells. Biosci Rep. doi: 10.1042/BSR20150217 PubMedPubMedCentralGoogle Scholar
  81. 81.
    Basu S, Golovina T, Mikheeva T, June CH, Riley JL (2008) Cutting edge: Foxp3-mediated induction of pim 2 allows human T regulatory cells to preferentially expand in rapamycin. J Immunol 180:5794–5798PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Zhang XH, Yu HL, Wang FJ, Han YL, Yang WL (2015) Pim-2 modulates aerobic glycolysis and energy production during the development of colorectal tumors. Int J Med Sci 12:487–493PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Zhang P, Wang H, Min X et al (2009) Pim-3 is expressed in endothelial cells and promotes vascular tube formation. J Cell Physiol 220:82–90PubMedCrossRefGoogle Scholar
  84. 84.
    Wang C, Li HY, Liu B, Huang S, Wu L, Li YY (2013) Pim-3 promotes the growth of human pancreatic cancer in the orthotopic nude mouse model through vascular endothelium growth factor. J Surg Res 185:595–604PubMedCrossRefGoogle Scholar
  85. 85.
    Quan J, Zhou L, Qu J (2015) Knockdown of Pim-3 suppresses the tumorigenicity of glioblastoma by regulating cell cycle and apoptosis. Cell Mol Biol 61:42–50PubMedGoogle Scholar
  86. 86.
    Cheng CK, Li L, Cheng SH et al (2008) Transcriptional repression of the RUNX3/AML2 gene by the t(8;21) and inv(16) fusion proteins in acute myeloid leukemia. Blood 112:3391–3402PubMedCrossRefGoogle Scholar
  87. 87.
    Siu A, Virtanen C, Jongstra J (2011) PIM kinase isoform specific regulation of MIG6 expression and EGFR signaling in prostate cancer cells. Oncotarget 2:1134–1144PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Wendt MK, Williams WK, Pascuzzi PE et al (2015) The antitumorigenic function of EGFR in metastatic breast cancer is regulated by expression of Mig6. Neoplasia 17:124–133PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Syed ZA, Yin W, Hughes K, Gill JN, Shi R, Clifford JL (2011) HGF/c-met/Stat3 signaling during skin tumor cell invasion: indications for a positive feedback loop. BMC Cancer 11:180PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Shen HB, Gu ZQ, Jian K, Qi J (2013) CXCR4-mediated Stat3 activation is essential for CXCL12-induced cell invasion in bladder cancer. Tumour Biol 34:1839–1845PubMedCrossRefGoogle Scholar
  91. 91.
    Liu X, Xiao Q, Bai X et al (2014) Activation of STAT3 is involved in malignancy mediated by CXCL12-CXCR4 signaling in human breast cancer. Oncol Rep 32:2760–2768PubMedGoogle Scholar
  92. 92.
    Wu J, Patmore DM, Jousma E et al (2014) EGFR-STAT3 signaling promotes formation of malignant peripheral nerve sheath tumors. Oncogene 33:173–180PubMedCrossRefGoogle Scholar
  93. 93.
    Choudhary C, Brandts C, Schwable J et al (2007) Activation mechanisms of STAT5 by oncogenic Flt3-ITD. Blood 110:370–374PubMedCrossRefGoogle Scholar
  94. 94.
    Nosaka T, Kawashima T, Misawa K, Ikuta K, Mui AL, Kitamura T (1999) STAT5 as a molecular regulator of proliferation, differentiation and apoptosis in hematopoietic cells. EMBO J 18:4754–4765PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Kim KT, Baird K, Ahn JY et al (2005) Pim-1 is up-regulated by constitutively activated FLT3 and plays a role in FLT3-mediated cell survival. Blood 105:1759–1767PubMedCrossRefGoogle Scholar
  96. 96.
    Walker SR, Nelson EA, Yeh JE, Pinello L, Yuan GC, Frank DA (2013) STAT5 outcompetes STAT3 to regulate the expression of the oncogenic transcriptional modulator BCL6. Mol Cell Biol 33:2879–2890PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Shortt J, Johnstone RW. (2012) Oncogenes in cell survival and cell death. Cold Spring Harb Perspect Biol. doi: 10.1101/cshperspect.a009829 PubMedPubMedCentralGoogle Scholar
  98. 98.
    Westphal D, Kluck RM, Dewson G (2014) Building blocks of the apoptotic pore: how Bax and Bak are activated and oligomerize during apoptosis. Cell Death Differ 21:196–205PubMedCrossRefGoogle Scholar
  99. 99.
    Harada H, Andersen JS, Mann M, Terada N, Korsmeyer SJ (2001) p70S6 kinase signals cell survival as well as growth, inactivating the pro-apoptotic molecule BAD. Proc Natl Acad Sci USA 98:9666–9670PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Song JH, An N, Chatterjee S et al (2015) Deletion of Pim kinases elevates the cellular levels of reactive oxygen species and sensitizes to K-Ras-induced cell killing. Oncogene 34:3728–3736PubMedCrossRefGoogle Scholar
  101. 101.
    Park MT, Kim MJ, Suh Y et al (2014) Novel signaling axis for ROS generation during K-Ras-induced cellular transformation. Cell Death Differ 21:1185–1197PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Jinesh GG, Taoka R, Zhang Q, Gorantla S, Kamat AM. (2016) Novel PKC-zeta to p47(phox) interaction is necessary for transformation from blebbishields. Sci Rep 6:23965PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Yuan ZQ, Feldman RI, Sussman GE, Coppola D, Nicosia SV, Cheng JQ (2003) AKT2 inhibition of cisplatin-induced JNK/p38 and Bax activation by phosphorylation of ASK1: implication of AKT2 in chemoresistance. J Biol Chem 278:23432–23440PubMedCrossRefGoogle Scholar
  104. 104.
    Juin P, Hunt A, Littlewood T et al (2002) c-Myc functionally cooperates with Bax to induce apoptosis. Mol Cell Biol 22:6158–6169PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Papa S, Skulachev VP (1997) Reactive oxygen species, mitochondria, apoptosis and aging. Mol Cell Biochem 174:305–319PubMedCrossRefGoogle Scholar
  106. 106.
    Lim CB, Prele CM, Baltic S et al (2015) Mitochondria-derived reactive oxygen species drive GANT61-induced mesothelioma cell apoptosis. Oncotarget 6:1519–1530PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Jinesh GG, Kamat AM. (2016) Endocytosis and serpentine filopodia drive blebbishield-mediated resurrection of apoptotic cancer stem cells. Cell Death Discov 1:15069CrossRefGoogle Scholar
  108. 108.
    Jinesh GG, Choi W, Shah JB, Lee EK, Willis DL, Kamat AM (2013) Blebbishields, the emergency program for cancer stem cells: sphere formation and tumorigenesis after apoptosis. Cell Death Differ 20:382–395PubMedCrossRefGoogle Scholar
  109. 109.
    Frank S, Gaume B, Bergmann-Leitner ES et al (2001) The role of dynamin-related protein 1, a mediator of mitochondrial fission, in apoptosis. Dev Cell 1:515–525PubMedCrossRefGoogle Scholar
  110. 110.
    Huang P, Galloway CA, Yoon Y (2011) Control of mitochondrial morphology through differential interactions of mitochondrial fusion and fission proteins. PloS One 6:e20655PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Din S, Mason M, Volkers M et al (2013) Pim-1 preserves mitochondrial morphology by inhibiting dynamin-related protein 1 translocation. Proc Natl Acad Sci USA 110:5969–5974PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Goodwin Jinesh G, Willis DL, Kamat AM. (2014) Bladder cancer stem cells: biological and therapeutic perspectives. Curr Stem Cell Res Ther 9:89–101PubMedCrossRefGoogle Scholar
  113. 113.
    Sukumar M, Liu J, Ji Y et al (2013) Inhibiting glycolytic metabolism enhances CD8+ T cell memory and antitumor function. J Clin Invest 123:4479–4488PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Haas R, Smith J, Rocher-Ros V, et al. (2015) Lactate regulates metabolic and pro-inflammatory circuits in control of T cell migration and effector functions. PLoS Biol 13:e1002202PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Fischer K, Hoffmann P, Voelkl S et al (2007) Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood 109:3812–3819PubMedCrossRefGoogle Scholar
  116. 116.
    De Rosa V, Galgani M, Porcellini A et al (2015) Glycolysis controls the induction of human regulatory T cells by modulating the expression of FOXP3 exon 2 splicing variants. Nat Immunol 16:1174–1184PubMedCrossRefGoogle Scholar
  117. 117.
    Jinesh GG, Kamat AM. (2012) Redirecting neutrophils against bladder cancer cells by BCG and Smac mimetic combination. Oncoimmunology 1:1161–1162CrossRefGoogle Scholar
  118. 118.
    Jinesh GG, Chunduru S, Kamat AM (2012) Smac mimetic enables the anticancer action of BCG-stimulated neutrophils through TNF-alpha but not through TRAIL and FasL. J Leukoc Biol 92:233–244CrossRefGoogle Scholar
  119. 119.
    Jinesh GG, Lee EK, Tran J, Kamat AM (2013) Lenalidomide augments the efficacy of bacillus Calmette-Guerin (BCG) immunotherapy in vivo. Urol Oncol 31:1676–1682PubMedCrossRefGoogle Scholar
  120. 120.
    Zhang Y, Wang Z, Li X, Magnuson NS (2008) Pim kinase-dependent inhibition of c-Myc degradation. Oncogene 27:4809–4819PubMedCrossRefGoogle Scholar
  121. 121.
    Forshell LP, Li Y, Forshell TZ et al (2011) The direct Myc target Pim3 cooperates with other Pim kinases in supporting viability of Myc-induced B-cell lymphomas. Oncotarget 2:448–460PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Arakaki R, Yamada A, Kudo Y, Hayashi Y, Ishimaru N (2014) Mechanism of activation-induced cell death of T cells and regulation of FasL expression. Crit Rev Immunol 34:301–314PubMedCrossRefGoogle Scholar
  123. 123.
    An N, Kraft AS, Kang Y (2013) Abnormal hematopoietic phenotypes in Pim kinase triple knockout mice. J Hematol Oncol 6:12PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Tran MN, Goodwin Jinesh G, McConkey DJ, Kamat AM. (2010) Bladder cancer stem cells. Curr Stem Cell Res Ther 5:387–395PubMedCrossRefGoogle Scholar
  125. 125.
    Giacomini KM, Huang SM, Tweedie DJ, et al. (2010) Membrane transporters in drug development. Nat Rev Drug Discov 9:215–236PubMedCrossRefGoogle Scholar
  126. 126.
    Xie Y, Burcu M, Linn DE, Qiu Y, Baer MR (2010) Pim-1 kinase protects P-glycoprotein from degradation and enables its glycosylation and cell surface expression. Mol Pharmacol 78:310–318PubMedCrossRefGoogle Scholar
  127. 127.
    Natarajan K, Bhullar J, Shukla S et al (2013) The Pim kinase inhibitor SGI-1776 decreases cell surface expression of P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) and drug transport by Pim-1-dependent and -independent mechanisms. Biochem Pharmacol 85:514–524PubMedCrossRefGoogle Scholar
  128. 128.
    Garcia PD, Langowski JL, Wang Y et al (2014) Pan-PIM kinase inhibition provides a novel therapy for treating hematologic cancers. Clin Cancer Res 20:1834–1845PubMedCrossRefGoogle Scholar
  129. 129.
    Yang Q, Chen LS, Neelapu SS, Miranda RN, Medeiros LJ, Gandhi V (2012) Transcription and translation are primary targets of Pim kinase inhibitor SGI-1776 in mantle cell lymphoma. Blood 120:3491–3500PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Mazzacurati L, Lambert QT, Pradhan A, Griner LN, Huszar D, Reuther GW (2015) The PIM inhibitor AZD1208 synergizes with ruxolitinib to induce apoptosis of ruxolitinib sensitive and resistant JAK2-V617F-driven cells and inhibit colony formation of primary MPN cells. Oncotarget 6:40141–40157PubMedPubMedCentralGoogle Scholar
  131. 131.
    Kreuz S, Holmes KB, Tooze RM, Lefevre PF (2015) Loss of PIM2 enhances the anti-proliferative effect of the pan-PIM kinase inhibitor AZD1208 in non-Hodgkin lymphomas. Mol Cancer 14:205PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Swords R, Kelly K, Carew J et al (2011) The Pim kinases: new targets for drug development. Curr Drug Targets 12:2059–2066PubMedCrossRefGoogle Scholar
  133. 133.
    Merkel AL, Meggers E, Ocker M (2012) PIM1 kinase as a target for cancer therapy. Expert Opin Investig Drugs 21:425–436PubMedCrossRefGoogle Scholar
  134. 134.
    Song JH, Kraft AS (2012) Pim kinase inhibitors sensitize prostate cancer cells to apoptosis triggered by Bcl-2 family inhibitor ABT-737. Cancer Res 72:294–303PubMedCrossRefGoogle Scholar
  135. 135.
    Ma J, Arnold HK, Lilly MB, Sears RC, Kraft AS (2007) Negative regulation of Pim-1 protein kinase levels by the B56beta subunit of PP2A. Oncogene 26:5145–5153PubMedCrossRefGoogle Scholar
  136. 136.
    Shen M, Stukenberg PT, Kirschner MW, Lu KP. (1998) The essential mitotic peptidyl-prolyl isomerase Pin1 binds and regulates mitosis-specific phosphoproteins. Gene Dev 12:706–720PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Li X, Liu Y, Chen W et al. (2014) TOP2Ahigh is the phenotype of recurrence and metastasis whereas TOP2Aneg cells represent cancer stem cells in prostate cancer. Oncotarget 5:9498–9513PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Wan S, Liu Y, Weng Y, et al. (2014) BMP9 regulates cross-talk between breast cancer cells and bone marrow-derived mesenchymal stem cells. Cell Oncol (Dordr) 37:363–375.CrossRefGoogle Scholar
  139. 139.
    Liang C, Yu XJ, Guo XZ et al (2015) MicroRNA-33a-mediated downregulation of Pim-3 kinase expression renders human pancreatic cancer cells sensitivity to gemcitabine. Oncotarget 6:14440–14455PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Thomas M, Lange-Grunweller K, Weirauch U et al (2012) The proto-oncogene Pim-1 is a target of miR-33a. Oncogene 31:918–928PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Goodwin G. Jinesh
    • 1
    Email author
  • Sharada Mokkapati
    • 1
  • Keyi Zhu
    • 1
  • Edwin E. Morales
    • 1
  1. 1.Department of UrologyThe University of Texas MD Anderson Cancer CenterHoustonUSA

Personalised recommendations