Autophagy pathway is required for IL-6 induced neuroendocrine differentiation and chemoresistance of prostate cancer LNCaP cells

Pei Ching Chang, Tao Yeuan Wang, Yi Ting Chang, Cheng Ying Chu, Chin Ling Lee, Hung Wei Hsu, Tyng An Zhou, Zhaoju Wu, Randie H. Kim, Sonal J. Desai, Shangqin Liu, Hsing Jien Kung

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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.

Original languageEnglish
Article numbere88556
JournalPLoS One
Volume9
Issue number2
DOIs
Publication statusPublished - Feb 14 2014

Fingerprint

autophagy
Autophagy
prostatic neoplasms
interleukin-6
Interleukin-6
Prostatic Neoplasms
Androgens
Tumors
AMP-Activated Protein Kinases
Chemical activation
androgens
Neuroendocrine Cells
Neuroendocrine Tumors
Tissue
Chromogranin A
Phosphorylation
Chemotherapy
neoplasm cells
neoplasms
Chloroquine

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Autophagy pathway is required for IL-6 induced neuroendocrine differentiation and chemoresistance of prostate cancer LNCaP cells. / Chang, Pei Ching; Wang, Tao Yeuan; Chang, Yi Ting; Chu, Cheng Ying; Lee, Chin Ling; Hsu, Hung Wei; Zhou, Tyng An; Wu, Zhaoju; Kim, Randie H.; Desai, Sonal J.; Liu, Shangqin; Kung, Hsing Jien.

In: PLoS One, Vol. 9, No. 2, e88556, 14.02.2014.

Research output: Contribution to journalArticle

Chang, Pei Ching ; Wang, Tao Yeuan ; Chang, Yi Ting ; Chu, Cheng Ying ; Lee, Chin Ling ; Hsu, Hung Wei ; Zhou, Tyng An ; Wu, Zhaoju ; Kim, Randie H. ; Desai, Sonal J. ; Liu, Shangqin ; Kung, Hsing Jien. / Autophagy pathway is required for IL-6 induced neuroendocrine differentiation and chemoresistance of prostate cancer LNCaP cells. In: PLoS One. 2014 ; Vol. 9, No. 2.
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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.",
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AU - Chu, Cheng Ying

AU - Lee, Chin Ling

AU - Hsu, Hung Wei

AU - Zhou, Tyng An

AU - Wu, Zhaoju

AU - Kim, Randie H.

AU - Desai, Sonal J.

AU - Liu, Shangqin

AU - Kung, Hsing Jien

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