Caveolin-1 functions as a key regulator of 17β-estradiol-mediated autophagy and apoptosis in BT474 breast cancer cells.

Estradiol (E2) acts as a crucial regulator of cell growth by mediating autophagy and apoptosis in breast cancer cells. Caveolin-1 plays a key role in carcinogenesis through its diverse roles in membrane trafficking, cholesterol transport and cellular signal transduction. However, it remains unknown as to how caveolin-1 is associated with E2-mediated autophagy and apoptosis in breast cancer cells. To resolve this issue, in the present study, we used the human breast cancer cell line, BT474, in which caveolin-1 is abundantly expressed. We demonstrated that treatment with E2 increased the expression of caveolin-1, high mobility group box 1 protein (HMGB1) and autophagy-related proteins [Beclin-1, light chain (LC3)-II and Atg12/5] in a time-dependent manner and inhibited the apoptosis of BT474 cells. Following the knockdown of caveolin-1 expression using small interfering RNA (siRNA), the expression of HMGB1, LC3-II and Atg12/5 was decreased, autophgosome formation was inhibited and apoptosis was induced; however, Beclin-1 expression was not affected. Furthermore, we knocked down HMGB1 to validate the role of HMGB1 in E2/caveolin‑1-regulated autophagy and apoptosis. Notably, the knockdown of HMGB1 decreased the expression of Beclin-1 and LC3-II and attenuated autophgosome formation and promoted apoptosis. Furthmore, caveolin-1 or HMGB1 knockdown markedly suppressed E2-induced cell growth. These results suggest that caveolin-1 is a positive regulator for E2-induced cell growth by promoting auptophagy and inhibiting apoptosis in BT474 cells.

[1]  J. Pouysségur,et al.  Hypoxia signalling in cancer and approaches to enforce tumour regression , 2006, Nature.

[2]  D. Tang,et al.  Targeting HMGB1-mediated autophagy as a novel therapeutic strategy for osteosarcoma , 2012, Autophagy.

[3]  C. Meyer,et al.  Caveolin-1 abrogates TGF-β mediated hepatocyte apoptosis , 2013, Cell Death and Disease.

[4]  Takeshi Noda,et al.  LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing , 2000, The EMBO journal.

[5]  D. Lin,et al.  Higher Expression of Caveolin-1 Inhibits Human Small Cell Lung Cancer (SCLC) Apoptosis In Vitro , 2012, Cancer investigation.

[6]  Takeshi Tokuhisa,et al.  The role of autophagy during the early neonatal starvation period , 2004, Nature.

[7]  Mattias Belting,et al.  Exosome Uptake Depends on ERK1/2-Heat Shock Protein 27 Signaling and Lipid Raft-mediated Endocytosis Negatively Regulated by Caveolin-1 , 2013, The Journal of Biological Chemistry.

[8]  K. Fung,et al.  Arenobufagin, a natural bufadienolide from toad venom, induces apoptosis and autophagy in human hepatocellular carcinoma cells through inhibition of PI3K/Akt/mTOR pathway. , 2013, Carcinogenesis.

[9]  M. Lisanti,et al.  Caveolins, a Family of Scaffolding Proteins for Organizing “Preassembled Signaling Complexes” at the Plasma Membrane* , 1998, The Journal of Biological Chemistry.

[10]  S. Chi,et al.  Caveolin-1 increases aerobic glycolysis in colorectal cancers by stimulating HMGA1-mediated GLUT3 transcription. , 2012, Cancer research.

[11]  M. Lotze,et al.  HMGB1 as an autophagy sensor in oxidative stress , 2011, Autophagy.

[12]  Estradiol inhibits osteoblast apoptosis via promotion of autophagy through the ER–ERK–mTOR pathway , 2013, Apoptosis.

[13]  L. Kirshenbaum,et al.  p53 Mediates Autophagy and Cell Death by a Mechanism Contingent On Bnip3 , 2013, Hypertension.

[14]  J. Guan,et al.  Pro-tumorigenic function of autophagy in mammary oncogenesis , 2012, Autophagy.

[15]  G. Rune,et al.  Estradiol responsiveness of synaptopodin in hippocampal neurons is mediated by estrogen receptor β , 2013, The Journal of Steroid Biochemistry and Molecular Biology.

[16]  Chih-Lung Lin,et al.  Inhibition of autophagy as a therapeutic strategy of iron-induced brain injury after hemorrhage , 2012, Autophagy.

[17]  Zhi-Min Liu,et al.  17β-Estradiol promotes the invasion and migration of nuclear estrogen receptor-negative breast cancer cells through cross-talk between GPER1 and CXCR1 , 2013, The Journal of Steroid Biochemistry and Molecular Biology.

[18]  P. Chanvorachote,et al.  Caveolin-1 sensitizes cisplatin-induced lung cancer cell apoptosis via superoxide anion-dependent mechanism , 2011, Molecular and Cellular Biochemistry.

[19]  A. Joubert,et al.  The in vitro effects of 2-methoxyestradiol-bis-sulphamate on cell numbers, membrane integrity and cell morphology, and the possible induction of apoptosis and autophagy in a non-tumorigenic breast epithelial cell line , 2010, Cellular & Molecular Biology Letters.

[20]  J. Balsinde,et al.  Caveolin-1 Deficiency Causes Cholesterol-Dependent Mitochondrial Dysfunction and Apoptotic Susceptibility , 2011, Current Biology.

[21]  E. White,et al.  Autophagy-Mediated Tumor Promotion , 2013, Cell.

[22]  N. Mizushima,et al.  A New Protein Conjugation System in Human , 1998, The Journal of Biological Chemistry.

[23]  M. Muders,et al.  Angiogenic growth factor axis in autophagy regulation , 2013, Autophagy.

[24]  K. Tracey,et al.  Endogenous HMGB1 regulates autophagy , 2010, The Journal of cell biology.

[25]  M. Robinson,et al.  Caveolin-1 Regulates the Delivery and Endocytosis of the Glutamate Transporter, Excitatory Amino Acid Carrier 1* , 2007, Journal of Biological Chemistry.

[26]  A. Nègre-Salvayre,et al.  TRPC1 is regulated by caveolin‐1 and is involved in oxidized LDL‐induced apoptosis of vascular smooth muscle cells , 2009, Journal of cellular and molecular medicine.

[27]  S. Ryter,et al.  Deadly triplex: Smoke, autophagy and apoptosis , 2011, Autophagy.

[28]  T. Thompson,et al.  Loss of caveolin‐1 in prostate cancer stroma correlates with reduced relapse‐free survival and is functionally relevant to tumour progression , 2013, The Journal of pathology.

[29]  J. Gustafsson,et al.  Rapid regulation of K(ATP) channel activity by 17{beta}-estradiol in pancreatic {beta}-cells involves the estrogen receptor {beta} and the atrial natriuretic peptide receptor. , 2009, Molecular endocrinology.

[30]  Jingyan Han,et al.  Caveolin-1 Protects against Sepsis by Modulating Inflammatory Response, Alleviating Bacterial Burden, and Suppressing Thymocyte Apoptosis* , 2010, The Journal of Biological Chemistry.

[31]  Jialin C. Zheng,et al.  Knockdown of TIGAR by RNA interference induces apoptosis and autophagy in HepG2 hepatocellular carcinoma cells. , 2013, Biochemical and biophysical research communications.

[32]  Saroj Nepal,et al.  Activation of Autophagy by Globular Adiponectin Attenuates Ethanol‐induced Apoptosis in HepG2 Cells , 2013, Biochimica et biophysica acta.

[33]  S. Chi,et al.  CAV1/caveolin 1 enhances aerobic glycolysis in colon cancer cells via activation of SLC2A3/GLUT3 transcription , 2012, Autophagy.

[34]  S. Kametaka,et al.  Apg14p and Apg6/Vps30p Form a Protein Complex Essential for Autophagy in the Yeast, Saccharomyces cerevisiae * , 1998, The Journal of Biological Chemistry.

[35]  T. Kang,et al.  Caveolin-1-dependent apoptosis induced by fibrin degradation products. , 2009, Blood.

[36]  Arunkumar Krishnan,et al.  Caveolin-1 promotes gastric cancer progression by up-regulating epithelial to mesenchymal transition by crosstalk of signalling mechanisms under hypoxic condition. , 2014, European journal of cancer.

[37]  L. Kirshenbaum,et al.  53 Mediates Autophagy and Cell Death by a Mechanism Contingent On Bnip 3 , 2022 .