title: Autophagy pathway is required for IL-6 induced neuroendocrine differentiation and chemoresistance of prostate cancer LNCaP cells.
abstract: Prostate cancer (PCa) cells undergoing neuroendocrine differentiation (NED) are clinically relevant to the development of relapsed castration-resistant PCa. Increasing evidences show that autophagy involves in the development of neuroendocrine (NE) tumors, including PCa. To clarify the effect of autophagy on NED, androgen-sensitive PCa LNCaP cells were examined. Treatment of LNCaP cells with IL-6 resulted in an induction of autophagy. In the absence of androgen, IL-6 caused an even stronger activation of autophagy. Similar result was identified in NED induction. Inhibition of autophagy with chloroquine (CQ) markedly decreased NED. This observation was confirmed by beclin1 and Atg5 silencing experiments. Further supporting the role of autophagy in NED, we found that LC3 was up-regulated in PCa tissue that had relapsed after androgen-deprivation therapy when compared with their primary tumor counterpart. LC3 staining in relapsed PCa tissue showed punctate pattern similar to the staining of chromogranin A (CgA), a marker for NED cells. Moreover, autophagy inhibition induced the apoptosis of IL-6 induced NE differentiated PCa cells. Consistently, inhibition of autophagy by knockdown of beclin1 or Atg5 sensitized NE differentiated LNCaP cells to etoposide, a chemotherapy drug. To identify the mechanisms, phosphorylation of IL-6 downstream targets was analyzed. An increase in phospho-AMPK and a decrease in phospho-mTOR were found, which implies that IL-6 regulates autophagy through the AMPK/mTOR pathway. Most important to this study is the discovery of REST, a neuronal gene-specific transcriptional repressor that is involved in autophagy activation. REST was down-regulated in IL-6 treatment. Knockdown experiments suggest that REST is critical to NED and autophagy activation by IL-6. Together, our studies imply that autophagy is involved in PCa progression and plays a cytoprotective role when NED is induced in PCa cells by IL-6 treatment. These results reveal the potential of targeting autophagy as part of a combined therapeutic regime for NE tumors.
authors.affiliation: Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan, R.O.C.
authors.forename: Pei-Ching
authors.initials: PC
authors.lastname: Chang
authors.affiliation: Department of Pathology, Mackay Medical College and Mackay Memorial Hospital, New Taipei City, Taiwan, R.O.C ; Mackay Junior College of Medicine, Nursing, and Management, New Taipei City, Taiwan, R.O.C.
authors.forename: Tao-Yeuan
authors.initials: TY
authors.lastname: Wang
authors.affiliation: Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan, R.O.C.
authors.forename: Yi-Ting
authors.initials: YT
authors.lastname: Chang
authors.affiliation: Institute for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan, R.O.C.
authors.forename: Cheng-Ying
authors.initials: CY
authors.lastname: Chu
authors.affiliation: Department of Pathology, Mackay Medical College and Mackay Memorial Hospital, New Taipei City, Taiwan, R.O.C ; Mackay Junior College of Medicine, Nursing, and Management, New Taipei City, Taiwan, R.O.C.
authors.forename: Chin-Ling
authors.initials: CL
authors.lastname: Lee
authors.affiliation: Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan, R.O.C.
authors.forename: Hung-Wei
authors.initials: HW
authors.lastname: Hsu
authors.affiliation: Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan, R.O.C.
authors.forename: Tyng-An
authors.initials: TA
authors.lastname: Zhou
authors.affiliation: Department of Biochemistry and Molecular Medicine, University of California Davis, Davis, California, United States of America ; UC Davis Cancer Center, University of California Davis, Davis, California, United States of America.
authors.forename: Zhaoju
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Department of Dermatology, New York University School of Medicine, New York, New York, United States of America.
authors.forename: Randie H
authors.initials: RH
authors.lastname: Kim
authors.affiliation: UC Davis Cancer Center, University of California Davis, Davis, California, United States of America.
authors.forename: Sonal J
authors.initials: SJ
authors.lastname: Desai
authors.affiliation: Department of Hematlogy, Zhongnan Hospital of Wuhan University, Wuhan, China.
authors.forename: Shangqin
authors.initials: S
authors.lastname: Liu
authors.affiliation: Institute for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan, R.O.C ; Department of Biochemistry and Molecular Medicine, University of California Davis, Davis, California, United States of America ; Division of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli County, Taiwan, R.O.C.
authors.forename: Hsing-Jien
authors.initials: HJ
authors.lastname: Kung
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D000728:Androgens / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics; D000071186:Beclin-1; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D002738:Chloroquine / Q000494:pharmacology; D019610:Cytoprotection / Q000187:drug effects / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008954:Models, Biological; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000473:pathology; D055099:Neuroendocrine Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D000099229:RE1-Silencing Transcription Factor
chemical_list: D000263:Adenylate Kinase; D000728:Androgens; D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; D002738:Chloroquine; D015850:Interleukin-6; D008565:Membrane Proteins; D012097:Repressor Proteins; D058570:TOR Serine-Threonine Kinases; D000099229:RE1-Silencing Transcription Factor; C491997:BECN1 protein, human; C546842:MTOR protein, human