Apoptosis induced by PGC-1β in breast cancer cells is mediated by the mTOR pathway

Wang,Libin; Liu,Qilun; Li,Fang; Qiu,Jing; Fan,Heng; Ma,Haibin; Zhu,Yongzhao; Wu,Ligang; Han,Xuebo; Yang,Zhihong; Jiang,Haifeng; Wei,Jun; Xia,Haibin

doi:10.3892/or.2013.2628

Apoptosis induced by PGC-1β in breast cancer cells is mediated by the mTOR pathway

Authors:
- Libin Wang
- Qilun Liu
- Fang Li
- Jing Qiu
- Heng Fan
- Haibin Ma
- Yongzhao Zhu
- Ligang Wu
- Xuebo Han
- Zhihong Yang
- Haifeng Jiang
- Jun Wei
- Haibin Xia
View Affiliations

Affiliations: Life Science College, Shaanxi Normal University, Xi'an 710062, P.R. China, Ningxia Human Stem Cells Institute of General Hospital, Fertility Conservation Laboratory of Ministry of Education, Ningxia Medical University, Yinchuan 750004, P.R. China, Maternity and Child Health Hospital of Ningxia Hui Autonomous Region, Yinchuan 750004, P.R. China, Department of Stomatology, Qingdao Municipal Hospital, Qingdao 266000, P.R. China
Published online on: July 18, 2013 https://doi.org/10.3892/or.2013.2628
Pages: 1631-1638

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The peroxisome proliferator-activated receptor-γ (PPAR-γ) coactivator-1β (PGC-1β) is a well-established regulator of mitochondrial biogenesis. However, the underlying mechanism of PGC-1β action remains elusive. This study reveals that knockdown of endogenous PGC-1β by short-hairpin RNA (shRNA) leads to a decrease in the expression of mammalian target of rapamycin (mTOR) pathway-related genes in MDA-MB-231 cells. After knockdown of PGC-1β, phosphorylation of AMP-activated protein kinase (AMPK), phosphorylation of Rictor on Thr1135, Raptor and S6 protein was inhibited. However, Akt phosphorylation on Ser473 was upregulated and cell apoptosis occurred. In particular, we demonstrate that the levels of PGC-1β and mTOR correlated with overall mitochondrial activity. These results provide new evidence that cell apoptosis is orchestrated by the balance between several signaling pathways, and that PGC-1β takes part in these events in breast cancer cells mediated by the mTOR signaling pathway.

View Figures

View References

1	Ginsburg OM and Love RR: Breast cancer: a neglected disease for the majority of affected women worldwide. Breast J. 17:289–295. 2011. View Article : Google Scholar : PubMed/NCBI
2	Lorico A and Rappa G: Phenotypic heterogeneity of breast cancer stem cells. J Oncol. 2011:1350392011. View Article : Google Scholar : PubMed/NCBI
3	Misra Y, Bentley PA, Bond JP, Tighe S, Hunter T and Zhao FQ: Mammary gland morphological and gene expression changes underlying pregnancy protection of breast cancer tumorigenesis. Physiol Genomics. 44:76–88. 2012. View Article : Google Scholar : PubMed/NCBI
4	Bray F, McCarron P and Parkin DM: The changing global patterns of female breast cancer incidence and mortality. Breast Cancer Res. 6:229–239. 2004. View Article : Google Scholar : PubMed/NCBI
5	Perou CM: Molecular stratification of triple-negative breast cancers. Oncologist. 16(Suppl 1): S61–S70. 2011. View Article : Google Scholar
6	Liu S and Wicha MS: Targeting breast cancer stem cells. J Clin Oncol. 28:4006–4401. 2010. View Article : Google Scholar : PubMed/NCBI
7	Tremblay AM and Giguère V: The NR3B subgroup: an ovERRview. Nucl Recept Signal. 5:1–11. 2007.
8	Hartlerode A, Odate S, Shim I, Brown J and Scully R: Cell cycle-dependent induction of homologous recombination by a tightly regulated I-SceI fusion protein. PloS One. 6:e165012011. View Article : Google Scholar : PubMed/NCBI
9	Vezina C, Kudelski A and Sehgal SN: Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J Antibiot (Tokyo). 28:721–726. 1975. View Article : Google Scholar : PubMed/NCBI
10	Cunningham JT, Rodgers JT, Arlow DH, Vazquez F, Mootha VK and Puigserver P: mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex. Nature. 450:736–740. 2007. View Article : Google Scholar : PubMed/NCBI
11	Kelly DP and Scarpulla RC: Transcriptional regulatory circuits controlling mitochondrial biogenesis and function. Genes Dev. 18:357–368. 2004. View Article : Google Scholar : PubMed/NCBI
12	Spiegelman BM: Transcriptional control of mitochondrial energy metabolism through the PGC1 coactivators. Novartis Found Symp. 287:60–69. 2007. View Article : Google Scholar : PubMed/NCBI
13	Arany Z, Lebrasseur N, Morris C, et al: The transcriptional coactivator PGC-1beta drives the formation of oxidative type IIX fibers in skeletal muscle. Cell Metab. 5:35–46. 2007. View Article : Google Scholar : PubMed/NCBI
14	Czubryt MP, McAnally J, Fishman GI and Olson EN: Regulation of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha) and mitochondrial function by MEF2 and HDAC5. Proc Natl Acad Sci USA. 100:1711–1716. 2003. View Article : Google Scholar : PubMed/NCBI
15	Attia RR, Connnaughton S, Boone LR, et al: Regulation of pyruvate dehydrogenase kinase 4 (PDK4) by thyroid hormone: role of the peroxisome proliferator-activated receptor gamma coactivator (PGC-1 alpha). J Biol Chem. 285:2375–2385. 2010. View Article : Google Scholar
16	Schieke SM, Phillips D, McCoy JP Jr, et al: The mammalian target of rapamycin (mTOR) pathway regulates mitochondrial oxygen consumption and oxidative capacity. J Biol Chem. 281:27643–27652. 2006. View Article : Google Scholar : PubMed/NCBI
17	Ramanathan A and Schreiber SL: Direct control of mitochondrial function by mTOR. Proc Natl Acad Sci USA. 106:22229–22232. 2009. View Article : Google Scholar : PubMed/NCBI
18	Wu Z, Puigserver P, Andersson U, et al: Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell. 98:115–124. 1999. View Article : Google Scholar : PubMed/NCBI
19	St-Pierre J, Lin J, Krauss S, et al: Bioenergetic analysis of peroxisome proliferator-activated receptor gamma coactivators 1alpha and 1beta (PGC-1alpha and PGC-1β) in muscle cells. J Biol Chem. 278:26597–26603. 2003.PubMed/NCBI
20	Hardie DG: Minireview: the AMP-activated protein kinase cascade: the key sensor of cellular energy status. Endocrinology. 144:5179–5183. 2003. View Article : Google Scholar : PubMed/NCBI
21	Kemp BE, Stapleton D, Campbell DJ, et al: AMP-activated protein kinase, super metabolic regulator. Biochem Soc Trans. 31:162–168. 2003. View Article : Google Scholar : PubMed/NCBI
22	Willer A: Reduction of the individual cancer risk by physical exercise. Onkologie. 26:283–289. 2003. View Article : Google Scholar : PubMed/NCBI
23	Gwinn DM, Shackelford DB, Egan DF, et al: AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell. 30:214–226. 2008. View Article : Google Scholar : PubMed/NCBI
25	Kabeya Y, Mizushima N, Ueno T, et al: LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J. 19:5720–5728. 2000.
24	Hardie DG, Salt IP, Hawley SA and Davies SP: AMP-activated protein kinase: an ultrasensitive system for monitoring cellular energy charge. Biochem J. 338:717–722. 1999. View Article : Google Scholar : PubMed/NCBI
26	Cao Y and Klionsky DJ: Physiological functions of Atg6/Beclin 1: a unique autophagy-related protein. Cell Res. 17:839–849. 2007. View Article : Google Scholar : PubMed/NCBI
27	Pattingre S, Espert L, Biard-Piechaczyk M and Codogno P: Regulation of macroautophagy by mTOR and Beclin 1 complexes. Biochimie. 90:313–323. 2008. View Article : Google Scholar : PubMed/NCBI
28	Meirhaeghe A, Crowley V, Lenaghan C, et al: Characterization of the human, mouse and rat PGC1 beta (peroxisome-proliferator-activated receptor-gamma co-activator 1 beta) gene in vitro and in vivo. Biochem J. 373:155–165. 2003. View Article : Google Scholar : PubMed/NCBI
29	Lin J, Tarr PT, Yang R, et al: PGC-1βeta in the regulation of hepatic glucose and energy metabolism. J Biol Chem. 278:30843–30848. 2003.
30	Finck BN and Kelly DP: PGC-1 coactivators: inducible regulators of energy metabolism in health and disease. J Clin Invest. 116:615–622. 2006. View Article : Google Scholar : PubMed/NCBI
31	Feige JN and Auwerx J: Transcriptional coregulators in the control of energy homeostasis. Trends Cell Biol. 17:292–301. 2007. View Article : Google Scholar : PubMed/NCBI
32	Peralba JM, DeGraffenried L, Friedrichs W, et al: Pharmacodynamic evaluation of CCI-779, an inhibitor of mTOR, in cancer patients. Clin Cancer Res. 9:2887–2892. 2003.PubMed/NCBI
33	Boulay A, Zumstein-Mecker S, Stephan C, et al: Antitumor efficacy of intermittent treatment schedules with the rapamycin derivative RAD001 correlates with prolonged inactivation of ribosomal protein S6 kinase 1 in peripheral blood mononuclear cells. Cancer Res. 64:252–261. 2004. View Article : Google Scholar
34	Basso AD, Mirza A, Liu G, Long BJ, Bishop WR and Kirschmeier P: The farnesyl transferase inhibitor (FTI) SCH66336 (lonafarnib) inhibits Rheb farnesylation and mTOR signaling. Role in FTI enhancement of taxane and tamoxifen anti-tumor activity. J Biol Chem. 280:31101–31108. 2005. View Article : Google Scholar : PubMed/NCBI
35	Harhaji-Trajkovic L, Vilimanovich U, Kravic-Stevovic T, Bumbasirevic V and Trajkovic V: AMPK-mediated autophagy inhibits apoptosis in cisplatin-treated tumour cells. J Cell Mol Med. 13:3644–3654. 2009. View Article : Google Scholar : PubMed/NCBI
36	Herrero-Martin G, Høyer-Hansen M, Garcia-Garcia C, et al: TAK1 activates AMPK-dependent cytoprotective autophagy in TRAIL-treated epithelial cells. EMBO J. 28:677–685. 2009. View Article : Google Scholar : PubMed/NCBI