Lactate promotes resistance to glucose starvation via upregulation of Bcl-2 mediated by mTOR activation

Huang,Chen; Sheng,Shile; Li,Rui; Sun,Xiaoguang; Liu,Jianju; Huang,Gang

doi:10.3892/or.2014.3655

Lactate promotes resistance to glucose starvation via upregulation of Bcl-2 mediated by mTOR activation

Authors:
- Chen Huang
- Shile Sheng
- Rui Li
- Xiaoguang Sun
- Jianju Liu
- Gang Huang
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Affiliations: Department of Nuclear Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, P.R. China, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine (SJTUSM) and Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), Shanghai 200025, P.R. China
Published online on: December 8, 2014 https://doi.org/10.3892/or.2014.3655
Pages: 875-884

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Abstract

Solid tumors grow faster and need more glucose than normal tissue; however, due to poor angiogenesis and excessive growth, tumors remote from blood vessels are always under glucose starvation. Even so, cancer cells remain alive in vivo. Thus, making cancer cells sensitive to glucose depletion may potentially provide an effective strategy for cancer intervention. Tumors that obtain sufficient glucose generate a large amount of lactate. Therefore, we proposed that lactate, a tumor microenvironment factor, may allow cancer cells to develop resistance to glucose starvation-induced death. We cultured cancer cells in no-glucose medium and added lactate to the medium. During the experiment, lactate helped cancer cells to escape from glucose starvation-induced cell death, without using lactate as an energy substrate, resulting in activation of Akt through PI3K. Akt activation plays a central role in cell growth through the activation of mammalian target of rapamycin (mTOR). Alteration of the PI3K/Akt/mTOR signaling pathway by inhibiting apoptosis induced specific upregulation of B-cell lymphoma 2 (Bcl-2) through translational control. In conclusion, this study showed that lactate rescues cancer cells from glucose starvation-induced cell death through regulation of the PI3K/Akt/mTOR/Bcl-2 signaling pathway. These data suggest that lactate is an important determinant of the sensitivity of tumors to glucose starvation, and reducing lactate or inhibiting the PI3K/Akt/mTOR/Bcl-2 signaling pathway may influence the response of cancers to glucose starvation.

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1	Vaupel P: Tumor microenvironmental physiology and its implications for radiation oncology. Semin Radiat Oncol. 14:198–206. 2004. View Article : Google Scholar : PubMed/NCBI
2	Hirayama A, Kami K, Sugimoto M, Sugawara M, Tok N, Onozuka H, Kinoshita T, Saito N, Ochiai A, Tomita M, Esumi H and Soga T: Quantitative metabolome profiling of colon and stomach cancer microenvironment by capillary electrophoresis time-of-flight mass spectrometry. Cancer Res. 69:4918–4925. 2009. View Article : Google Scholar : PubMed/NCBI
3	Hahnfeldt P, Panigrahy D, Folkman J and Hlatky L: Tumor development under angiogenic signaling: a dynamical theory of tumor growth, treatment response, and postvascular dormancy. Cancer Res. 59:4770–4775. 1999.PubMed/NCBI
4	Warburg O: On respiratory impairment in cancer cells. Science. 124:269–270. 1956.PubMed/NCBI
5	Hanahan D and Weinberg RA: Hallmarks of cancer: The next generation. Cell. 144:646–674. 2011. View Article : Google Scholar : PubMed/NCBI
6	Quennet V, Yaromina A, Zips D, Rosner A, Walenta S, Baumann M and Mueller-Klieser W: Tumor lactate content predicts for response to fractionated irradiation of human squamous cell carcinomas in nude mice. Radiother Oncol. 81:130–135. 2006. View Article : Google Scholar : PubMed/NCBI
7	Brizel DM, Schroeder T, Scher RL, Walenta S, Clough RW, Dewhirst MW and Mueller-Klieser W: Elevated tumor lactate concentrations predict for an increased risk of metastases in head-and-neck cancer. Int J Radiat Oncol Biol Phys. 51:349–353. 2001. View Article : Google Scholar : PubMed/NCBI
8	Gottfried E, Kunz-Schughart LA, Ebner S, Mueller-Klieser W, Hoves S, Andreesen R, Mackensen A and Kreutz M: Tumor-derived lactic acid modulates dendritic cell activation and antigen expression. Blood. 107:2013–2021. 2006. View Article : Google Scholar
9	Fischer K, Hoffmann P, Voelkl S, Meidenbauer N, Ammer J, Edinger M, Gottfried E, Schwarz S, Rothe G, Hoves S, Renner K, Timischl B, Mackensen A, Kunz-Schughart L, Andreesen R, Krause SW and Kreutz M: Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood. 109:3812–3819. 2007. View Article : Google Scholar : PubMed/NCBI
10	Goetze K, Walenta S, Ksiazkiewicz M, Kunz-Schughart LA and Mueller-Klieser W: Lactate enhances motility of tumor cells and inhibits monocyte migration and cytokine release. Int J Oncol. 39:453–463. 2011.PubMed/NCBI
11	Sattler UG, Meyer SS, Quennet V, Hoerner C, Knoerzer H, Fabian C, Yaromina A, Zips D, Walenta S, Baumann M and Mueller-Klieser W: Glycolytic metabolism and tumour response to fractionated irradiation. Radiother Oncol. 94:102–109. 2010. View Article : Google Scholar
12	Le A, Cooper CR, Gouw AM, Dinavahi R, Maitra A, Deck LM, Royer RE, Vander Jagt DL, Semenza GL and Dang CV: Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression. Proc Natl Acad Sci USA. 107:2037–2042. 2010. View Article : Google Scholar : PubMed/NCBI
13	Sharrard RM and Maitland NJ: Regulation of protein kinase B activity by PTEN and SHIP2 in human prostate-derived cell lines. Cell Signal. 19:129–138. 2007. View Article : Google Scholar
14	Osaki M, Oshimura M and Ito H: PI3K-Akt pathway: its functions and alterations in human cancer. Apoptosis. 9:667–676. 2004. View Article : Google Scholar : PubMed/NCBI
15	Gambhir SS, Czernin J, Schwimmer J, Silverman DH, Coleman RE and Phelps ME: A tabulated summary of the FDG PET literature. J Nucl Med. 42(Suppl 5): 1S–93S. 2001.PubMed/NCBI
16	Walenta S, Wetterling M, Lehrke M, Schwickert G, Sundfør K, Rofstad EK and Mueller-Klieser W: High lactate levels predict likelihood of metastases, tumor recurrence, and restricted patient survival in human cervical cancers. Cancer Res. 60:916–921. 2000.PubMed/NCBI
17	Brizel DM, Schroeder T, Scher RL, Walenta S, Clough RW, Dewhirst MW and Mueller-Klieser W: Elevated tumor lactate concentrations predict for an increased risk of metastases in head-and-neck cancer. Int J Radiat Oncol Biol Phys. 51:349–353. 2001. View Article : Google Scholar : PubMed/NCBI
18	Walenta S, Chau TV, Schroeder T, Lehr HA, Kunz-Schughart LA, Fuerst A and Mueller-Klieser W: Metabolic classification of human rectal adenocarcinomas: a novel guideline for clinical oncologists? J Cancer Res Clin Oncol. 129:321–326. 2003. View Article : Google Scholar : PubMed/NCBI
19	Sheng SL, Liu JJ, Dai YH, Sun XG, Xiong XP and Huang G: Knockdown of lactate dehydrogenase A suppresses tumor growth and metastasis of human hepatocellular carcinoma. FEBS J. 279:3898–3910. 2012. View Article : Google Scholar : PubMed/NCBI
20	Yokota H, Guo J, Matoba M, Higashi K, Tonami H and Nagao Y: Lactate, choline, and creatine levels measured by vitro 1H-MRS as prognostic parameters in patients with non-small-cell lung cancer. J Magn Reson Imaging. 25:992–999. 2007. View Article : Google Scholar : PubMed/NCBI
21	Semenza GL: Tumor metabolism: cancer cells give and take lactate. J Clin Invest. 118:3835–3837. 2008.PubMed/NCBI
22	Bonuccelli G, Tsirigos A, Whitaker-Menezes D, Pavlides S, Pestell RG, Chiavarina B, Frank PG, Flomenberg N, Howell A, Martinez-Outschoorn UE, Sotgia F and Lisanti MP: Ketones and lactate ‘fuel’ tumor growth and metastasis: Evidence that epithelial cancer cells use oxidative mitochondrial metabolism. Cell Cycle. 9:3506–3514. 2010. View Article : Google Scholar : PubMed/NCBI
23	Vegran F, Boidot R, Michiels C, Sonveaux P and Feron O: Lactate influx through the endothelial cell monocarboxylate transporter MCT1 supports an NF-κB/IL-8 pathway that drives tumor angiogenesis. Cancer Res. 71:2550–2560. 2011. View Article : Google Scholar
24	Trabold O, Wagner S, Wicke C, Scheuenstuhl H, Hussain MZ, Rosen N, Seremetiev A, Becker HD and Hunt TK: Lactate and oxygen constitute a fundamental regulatory mechanism in wound healing. Wound Repair Regen. 11:504–509. 2003. View Article : Google Scholar : PubMed/NCBI
25	Hunt TK, Aslam R, Hussain Z and Beckert S: Lactate, with oxygen, incites angiogenesis. Adv Exp Med Biol. 614:73–80. 2008. View Article : Google Scholar : PubMed/NCBI
26	Wu H, Ding Z, Hu D, Sun F, Dai C, Xie J and Hu X: Central role of lactic acidosis in cancer cell resistance to glucose deprivation-induced cell death. J Pathol. 227:189–199. 2012. View Article : Google Scholar
27	Kalaany NY and Sabatini DM: Tumours with PI3K activation are resistant to dietary restriction. Nature. 458:725–731. 2009. View Article : Google Scholar : PubMed/NCBI
28	Hashimoto T, Hussien R, Oommen S, Gohil K and Brooks GA: Lactate sensitive transcription factor network in L6 cells: activation of MCT1 and mitochondrial biogenesis. FASEB J. 21:2602–2612. 2007. View Article : Google Scholar : PubMed/NCBI
29	Lu H, Forbes RA and Verma A: Hypoxia-inducible factor 1 activation by aerobic glycolysis implicates the Warburg effect in carcinogenesis. J Biol Chem. 277:23111–23115. 2002. View Article : Google Scholar : PubMed/NCBI
30	Samuvel DJ, Sundararaj KP, Nareika A, Lopes-Virella MF and Huang Y: Lactate boosts TLR4 signaling and NF-kappaB pathwaymediated gene transcription in macrophages via monocarboxylate transporters and MD-2 up-regulation. J Immunol. 182:2476–2484. 2009. View Article : Google Scholar : PubMed/NCBI
31	Baumann F, Leukel P, Doerfelt A, Beier CP, Dettmer K, Oefner PJ, Kastenberger M, Kreutz M, Nickl-Jockschat T, Bogdahn U, Bosserhoff AK and Hau P: Lactate promotes glioma migration by TGF-beta2-dependent regulation of matrix metalloproteinase-2. Neuro Oncol. 11:368–380. 2009. View Article : Google Scholar :
32	Cory S and Adams JM: The Bcl2 family: regulators of the cellular life-or-death switch. Nat Rev Cancer. 2:647–656. 2002. View Article : Google Scholar : PubMed/NCBI
33	Song G, Ouyang GL and Bao SD: The activation of Akt/PKB signaling pathway and cell survival. J Cell Mol Med. 9:59–71. 2005. View Article : Google Scholar : PubMed/NCBI
34	Jeong SJ, Pise-Masison CA, Radonovich MF, Park HU and Brady JN: Activated Akt regulates NF-kappaB activation, p53 inhibition and cell survival in HTLV-1-transformed cells. Oncogene. 24:6719–6728. 2005. View Article : Google Scholar : PubMed/NCBI
35	Kim EC, Yun BS, Ryoo IJ, Min JK, Won MH, Lee KS, Kim YM, Yoo I and Kwon YG: Complestatin prevents apoptotic cell death: inhibition of a mitochondrial caspase pathway through AKT/PKB activation. Biochem Biophys Res Commun. 313:193–204. 2004. View Article : Google Scholar