Autophagy plays an important role in prostate cancer development. It promotes tumor cell survival and was found to be associated with androgen pathway. In the present study, we found that GABA(A) receptor-associated protein like 1 (Gabarapl1), a ubiquitin-like modifier, participates in the regulation of autophagy. Gabarapl1 is transcriptionally regulated by androgen receptor (AR) and has a repressive role in autophagy. Androgen deprivation downregulates Gabarapl1 in an AR dependent manner, resulting in the increase of autophagy flux. Elevated Gabarapl1 also represses the proliferation of prostate cancer cells. In summary, our study provides evidence to show that Gabarapl1 is a mediator involved in androgen-regulated autophagy process.
Gabarapl1 Autophagy Androgen Prostate cancer
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The study was supported by National Science Foundation (81272380) and Shenzhen Emerging Industry Foundation (JCYJ20130329110752141).
Conflicts of interest
Codogno P, Mehrpour M, Proikas-Cezanne T. Canonical and non-canonical autophagy: variations on a common theme of self-eating? Nat Rev Mol Cell Biol. 2012;13:7–12.Google Scholar
Alers S, Loffler AS, Wesselborg S, Stork B. Role of AMPK-mTOR-Ulk1/2 in the regulation of autophagy: cross talk, shortcuts, and feedbacks. Mol Cell Biol. 2012;32:2–11.CrossRefPubMedPubMedCentralGoogle Scholar
Rubinsztein DC. The roles of intracellular protein-degradation pathways in neurodegeneration. Nature. 2006;443:780–6.CrossRefPubMedGoogle Scholar
Yue Z, Jin S, Yang C, et al. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc Natl Acad Sci U S A. 2003;100:15077–82.CrossRefPubMedPubMedCentralGoogle Scholar
Shi Y, Han JJ, Tennakoon JB, et al. Androgens promote prostate cancer cell growth through induction of autophagy. Mol Endocrinol. 2013;27:280–95.CrossRefPubMedGoogle Scholar
Li M, Jiang X, Liu D, et al. Autophagy protects LNCaP cells under androgen deprivation conditions. Autophagy. 2008;4:54–60.CrossRefPubMedGoogle Scholar
Boyer-Guittaut M, Poillet L, Liang Q, et al. The role of GABARAPL1/GEC1 in autophagic flux and mitochondrial quality control in MDA-MB-436 breast cancer cells. Autophagy. 2014;10:986–1003.CrossRefPubMedPubMedCentralGoogle Scholar
Chen C, Li JG, Chen Y, et al. GEC1 interacts with the kappa opioid receptor and enhances expression of the receptor. J Biol Chem. 2006;281:7983–93.CrossRefPubMedGoogle Scholar
Chakrama FZ, Seguin-Py S, Le Grand JN, et al. GABARAPL1 (GEC1) associates with autophagic vesicles. Autophagy. 2010;6:495–505.CrossRefPubMedGoogle Scholar
Weidberg H, Shvets E, Shpilka T, et al. LC3 and GATE-16/GABARAP subfamilies are both essential yet act differently in autophagosome biogenesis. Embo j. 2010;29:1792–802.CrossRefPubMedPubMedCentralGoogle Scholar
Le Grand JN, Chakrama FZ, Seguin-Py S, et al. GABARAPL1 (GEC1): original or copycat? Autophagy. 2011;7:1098–107.CrossRefPubMedGoogle Scholar
Berthier A, Seguin S, Sasco AJ, et al. High expression of Gabarapl1 is associated with a better outcome for patients with lymph node-positive breast cancer. Br J Cancer. 2010;102:1024–31.CrossRefPubMedPubMedCentralGoogle Scholar
Jiang Q, Yeh S, Wang X, et al. Targeting androgen receptor leads to suppression of prostate cancer via induction of autophagy. J Urol. 2012;188:1361–8.CrossRefPubMedGoogle Scholar
Nguyen HG, Yang JC, Kung HJ, et al. Targeting autophagy overcomes enzalutamide resistance in castration-resistant prostate cancer cells and improves therapeutic response in a xenograft model. Oncogene. 2014;33:4521–30.CrossRefPubMedPubMedCentralGoogle Scholar