title: IL-4 induces proliferation in prostate cancer PC3 cells under nutrient-depletion stress through the activation of the JNK-pathway and survivin up-regulation.
abstract: Interleukin (IL)-4 plays a critical role in the regulation of immune responses and has been detected at high levels in the tumor microenvironment of cancer patients where it correlates with the grade of malignancy. The direct effect of IL-4 on cancer cells has been associated with increased cell survival; however, its role in cancer cell proliferation and related mechanisms is still unclear. Here it was shown that in a nutrient-depleted environment, IL-4 induces proliferation in prostate cancer PC3 cells. In these cells, under nutrient-depletion stress, IL-4 activates mitogen-activated protein kinases (MAPKs), including Erk, p38, and JNK. Using MAP-signaling-specific inhibitors, it was shown that IL-4-induced proliferation is mediated by JNK activation. In fact, JNK-inhibitor-V (JNKi-V) stunted IL-4-mediated cell proliferation. Furthermore, it was found that IL-4 induces survivin up-regulation in nutrient-depleted cancer cells. Using survivin-short-hairpin-RNAs (shRNAs), it was demonstrated that in this milieu survivin expression above a threshold limit is critical to the mechanism of IL-4-mediated proliferation. In addition, the significance of survivin up-regulation in a stressed environment was assessed in prostate cancer mouse xenografts. It was found that survivin knockdown decreases tumor progression in correlation with cancer cell proliferation. Furthermore, under nutrient depletion stress, IL -4 could induce proliferation in cancer cells from multiple origins: MDA-MB-231 (breast), A253 (head and neck), and SKOV-3 (ovarian). Overall, these findings suggest that in a tumor microenvironment under stress conditions, IL-4 triggers a simultaneous activation of the JNK-pathway and the up-regulation of survivin turning on a cancer proliferation mechanism.
authors.affiliation: Department of Urology, Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, USA. rocach@umich.edu
authors.forename: Hernan
authors.initials: H
authors.lastname: Roca
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Craig
authors.forename: Chi
authors.initials: C
authors.lastname: Ying
authors.forename: Zachary S
authors.initials: ZS
authors.lastname: Varsos
authors.forename: Paul
authors.initials: P
authors.lastname: Czarnieski
authors.forename: Ajjai S
authors.initials: AS
authors.lastname: Alva
authors.forename: James
authors.initials: J
authors.lastname: Hernandez
authors.forename: David
authors.initials: D
authors.lastname: Fuller
authors.forename: Stephanie
authors.initials: S
authors.lastname: Daignault
authors.forename: Patrick N
authors.initials: PN
authors.lastname: Healy
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Pienta
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D015847:Interleukin-4 / Q000494:pharmacology / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological; D000077022:Survivin; D014183:Transplantation, Heterologous; D059016:Tumor Microenvironment; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C107489:BIRC5 protein, human; C508598:IL4 protein, human; D051034:Inhibitor of Apoptosis Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D000077022:Survivin; D015847:Interleukin-4