Both IGF1R and INSR Knockdown Exert Antitumorigenic Effects in Prostate Cancer In Vitro and In Vivo

The IGF network with its main receptors IGF receptor 1 (IGF1R) and insulin receptor (INSR) is of major importance for cancer initiation and progression. To date, clinical studies targeting this network were disappointing and call for thorough analysis of the IGF network in cancer models. We highlight the oncogenic effects controlled by IGF1R and INSR in prostate cancer cells and show similarities as well as differences after receptor knockdown (KD). In PC3 prostate cancer cells stably transduced with inducible short hairpin RNAs, targeting IGF1R or INSR attenuated cell growth and proliferation ultimately driving cells into apoptosis. IGF1R KD triggered rapid and strong antiproliferative and proapoptotic responses, whereas these effects were less pronounced and delayed after INSR KD. Down-regulation of the antiapoptotic proteins myeloid cell leukemia-1 and survivin was observed in both KDs, whereas IGF1R KD also attenuated expression of prosurvival proteins B cell lymphoma-2 and B cell lymphoma-xL. Receptor KD induced cell death involved autophagy in particular upon IGF1R KD; however, no difference in mitochondrial energy metabolism was observed. In a mouse xenograft model, induction of IGF1R or INSR KD after tumor establishment eradicated most of the tumors. After 20 days of receptor KD, tumor cells were found only in 1/14 IGF1R and 3/14 INSR KD tumor remnants. Collectively, our data underline the oncogenic functions of IGF1R and INSR in prostate cancer namely growth, proliferation, and survival in vitro as well as in vivo and identify myeloid cell leukemia-1 and survivin as important mediators of inhibitory and apoptotic effects.

[1]  H. Klocker,et al.  The insulin-like growth factor (IGF) axis as an anticancer target in prostate cancer. , 2015, Cancer letters.

[2]  H. Klocker,et al.  Mechanistic rationale for MCL1 inhibition during androgen deprivation therapy , 2015, OncoTarget.

[3]  Keunchil Park,et al.  Randomized, phase III trial of first-line figitumumab in combination with paclitaxel and carboplatin versus paclitaxel and carboplatin alone in patients with advanced non-small-cell lung cancer. , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[4]  Helmut Klocker,et al.  Oncogenic functions of IGF1R and INSR in prostate cancer include enhanced tumor growth, cell migration and angiogenesis , 2014, Oncotarget.

[5]  F. Saad,et al.  Phase II Randomized Study of Figitumumab plus Docetaxel and Docetaxel Alone with Crossover for Metastatic Castration-Resistant Prostate Cancer , 2014, Clinical Cancer Research.

[6]  Eric H. Baehrecke,et al.  Self-consumption: the interplay of autophagy and apoptosis , 2014, Nature Reviews Molecular Cell Biology.

[7]  H. Klocker,et al.  Attenuation of nucleoside and anti-cancer nucleoside analog drug uptake in prostate cancer cells by Cimicifuga racemosa extract BNO-1055. , 2013, Phytomedicine : international journal of phytotherapy and phytopharmacology.

[8]  D. Newmeyer,et al.  The rheostat in the membrane: BCL-2 family proteins and apoptosis , 2013, Cell Death and Differentiation.

[9]  Tao Zhang,et al.  A Novel Small-Molecule Inhibitor of Mcl-1 Blocks Pancreatic Cancer Growth In Vitro and In Vivo , 2013, Molecular Cancer Therapeutics.

[10]  Kyle C. Nelson,et al.  BAD Dephosphorylation and Decreased Expression of MCL-1 Induce Rapid Apoptosis in Prostate Cancer Cells , 2013, PloS one.

[11]  Chun-Peng Liao,et al.  Loss of Survivin in the Prostate Epithelium Impedes Carcinogenesis in a Mouse Model of Prostate Adenocarcinoma , 2013, PloS one.

[12]  D. Altieri.  Targeting survivin in cancer. , 2013, Cancer letters.

[13]  D. Danielpour,et al.  Critical Role of a Survivin/TGF-β/mTORC1 Axis in IGF-I-Mediated Growth of Prostate Epithelial Cells , 2013, PloS one.

[14]  J. Rathmell,et al.  Metabolic stress in autophagy and cell death pathways. , 2012, Cold Spring Harbor perspectives in biology.

[15]  V. Rotter,et al.  Diverse functions of IGF/insulin signaling in malignant and noncancerous prostate cells: proliferation in cancer cells and differentiation in noncancerous cells. , 2012, Endocrinology.

[16]  J. Melamed,et al.  Paxillin mediates extranuclear and intranuclear signaling in prostate cancer proliferation. , 2012, The Journal of clinical investigation.

[17]  A. Tinker,et al.  A Phase II Pharmacodynamic Study of Preoperative Figitumumab in Patients with Localized Prostate Cancer , 2012, Clinical Cancer Research.

[18]  H. Klocker,et al.  PIAS1 is increased in human prostate cancer and enhances proliferation through inhibition of p21. , 2012, The American journal of pathology.

[19]  G. Giaccone,et al.  A phase II study of YM155, a novel small-molecule suppressor of survivin, in castration-resistant taxane-pretreated prostate cancer. , 2012, Annals of oncology : official journal of the European Society for Medical Oncology.

[20]  H. Klocker,et al.  Expression of the IGF axis is decreased in local prostate cancer but enhanced after benign prostate epithelial differentiation and TGF-β treatment. , 2011, American Journal of Pathology.

[21]  D. Leroith,et al.  Minireview: IGF, Insulin, and Cancer. , 2011, Endocrinology.

[22]  H. Klocker,et al.  Targeting the insulin-like growth factor network in cancer therapy , 2011, Cancer biology & therapy.

[23]  John Calvin Reed,et al.  A survey of the anti-apoptotic Bcl-2 subfamily expression in cancer types provides a platform to predict the efficacy of Bcl-2 antagonists in cancer therapy , 2010, Cell Death and Disease.

[24]  T. Hunt,et al.  Loss of the mammalian APC/C activator FZR1 shortens G1 and lengthens S phase but has little effect on exit from mitosis , 2009, Journal of Cell Science.

[25]  L. Kenner,et al.  Down-regulation of suppressor of cytokine signaling-3 causes prostate cancer cell death through activation of the extrinsic and intrinsic apoptosis pathways. , 2009, Cancer research.

[26]  Ivan Dikic,et al.  NBR1 and p62 as cargo receptors for selective autophagy of ubiquitinated targets , 2009, Cell cycle.

[27]  X. Hao,et al.  Knockdown of survivin expression by siRNAs enhances chemosensitivity of prostate cancer cells and attenuates its tumorigenicity. , 2009, Acta biochimica et biophysica Sinica.

[28]  Bruce Montgomery,et al.  Androgen deprivation therapy: progress in understanding mechanisms of resistance and optimizing androgen depletion , 2009, Nature Clinical Practice Urology.

[29]  Y. Sekine,et al.  Gene expression of survivin and its spliced isoforms associated with proliferation and aggressive phenotypes of prostate cancer. , 2008, Urology.

[30]  G. Kroemer,et al.  Bcl-2 family members: Dual regulators of apoptosis and autophagy , 2008, Autophagy.

[31]  William A Weiss,et al.  Recognizing and exploiting differences between RNAi and small-molecule inhibitors. , 2007, Nature chemical biology.

[32]  S. Hatakeyama,et al.  YM155, a novel small-molecule survivin suppressant, induces regression of established human hormone-refractory prostate tumor xenografts. , 2007, Cancer research.

[33]  Guido Kroemer,et al.  Self-eating and self-killing: crosstalk between autophagy and apoptosis , 2007, Nature Reviews Molecular Cell Biology.

[34]  J. Xiang,et al.  Up-regulation of Bcl-2 is required for the progression of prostate cancer cells from an androgen-dependent to an androgen-independent growth stage , 2007, Cell Research.

[35]  D. Leroith,et al.  The role of the IGF system in cancer growth and metastasis: overview and recent insights. , 2007, Endocrine reviews.

[36]  B. Aggarwal,et al.  Inflammation and cancer: how hot is the link? , 2006, Biochemical pharmacology.

[37]  N. Kyprianou,et al.  Growth factor signalling in prostatic growth: significance in tumour development and therapeutic targeting , 2006, British journal of pharmacology.

[38]  K. Podar,et al.  Mcl-1 Regulation and Its Role in Multiple Myeloma , 2004, Cell cycle.

[39]  H. Shiina,et al.  Expression of the survivin gene in prostate cancer: correlation with clinicopathological characteristics, proliferative activity and apoptosis. , 2004, The Journal of urology.

[40]  C. Roehrborn,et al.  Survivin expression is associated with features of biologically aggressive prostate carcinoma , 2004, Cancer.

[41]  M. Gishizky,et al.  Identification of structural characteristics that contribute to a difference in antiapoptotic function between human insulin and insulin-like growth factor 1 receptors. , 1998, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[42]  J. Trapman,et al.  Frequent inactivation of PTEN in prostate cancer cell lines and xenografts. , 1998, Cancer research.

[43]  L. Sepp-Lorenzino.  Structure and function of the insulin-like growth factor I receptor , 1998, Breast Cancer Research and Treatment.

[44]  M. Rubini,et al.  The IGF-I receptor in cell growth, transformation and apoptosis. , 1997, Biochimica et biophysica acta.

[45]  John Calvin Reed,et al.  Immunohistochemical analysis of bcl-2, bax, bcl-X, and mcl-1 expression in prostate cancers. , 1996, The American journal of pathology.

[46]  M. Campbell,et al.  Expression of the protooncogene bcl-2 in the prostate and its association with emergence of androgen-independent prostate cancer. , 1992, Cancer research.

[47]  A. Jemal,et al.  Cancer statistics, 2014 , 2014, CA: a cancer journal for clinicians.

[48]  E. Gnaiger,et al.  High-resolution respirometry: OXPHOS protocols for human cells and permeabilized fibers from small biopsies of human muscle. , 2012, Methods in molecular biology.

[49]  T. Ueno,et al.  LC3 and Autophagy. , 2008, Methods in molecular biology.

[50]  R. Margreiter,et al.  Mitochondria in the Cold , 2000 .

[51]  G Bartsch,et al.  Epidermal growth factor (EGF) receptor blockade inhibits the action of EGF, insulin-like growth factor I, and a protein kinase A activator on the mitogen-activated protein kinase pathway in prostate cancer cell lines. , 1999, Cancer research.