Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Molecular Cancer
Published in: Molecular Cancer 1/2010

Open Access 01-12-2010 | Research

Warburg effect in chemosensitivity: Targeting lactate dehydrogenase-A re-sensitizes Taxol-resistant cancer cells to Taxol

Authors: Ming Zhou, Yuhua Zhao, Yan Ding, Hao Liu, Zixing Liu, Oystein Fodstad, Adam I Riker, Sushama Kamarajugadda, Jianrong Lu, Laurie B Owen, Susan P Ledoux, Ming Tan

Published in: Molecular Cancer | Issue 1/2010

Login to get access

Abstract

Background

Taxol is one of the most effective chemotherapeutic agents for the treatment of patients with breast cancer. Despite impressive clinical responses initially, the majority of patients eventually develop resistance to Taxol. Lactate dehydrogenase-A (LDH-A) is one of the predominant isoforms of LDH expressed in breast tissue, which controls the conversion of pyruvate to lactate and plays an important role in glucose metabolism. In this study we investigated the role of LDH-A in mediating Taxol resistance in human breast cancer cells.

Results

Taxol-resistant subclones, derived from the cancer cell line MDA-MB-435, sustained continuous growth in high concentrations of Taxol while the Taxol-sensitive cells could not. The increased expression and activity of LDH-A were detected in Taxol-resistant cells when compared with their parental cells. The downregulation of LDH-A by siRNA significantly increased the sensitivity of Taxol-resistant cells to Taxol. A higher sensitivity to the specific LDH inhibitor, oxamate, was found in the Taxol-resistant cells. Furthermore, treating cells with the combination of Taxol and oxamate showed a synergistical inhibitory effect on Taxol-resistant breast cancer cells by promoting apoptosis in these cells.

Conclusion

LDH-A plays an important role in Taxol resistance and inhibition of LDH-A re-sensitizes Taxol-resistant cells to Taxol. This supports that Warburg effect is a property of Taxol resistant cancer cells and may play an important role in the development of Taxol resistance. To our knowledge, this is the first report showing that the increased expression of LDH-A plays an important role in Taxol resistance of human breast cancer cells. This study provides valuable information for the future development and use of targeted therapies, such as oxamate, for the treatment of patients with Taxol-resistant breast cancer.
Appendix
Available only for authorised users
Literature
1.
Henley D, Isbill M, Fernando R, Foster JS, Wimalasena J: Paclitaxel induced apoptosis in breast cancer cells requires cell cycle transit but not Cdc2 activity. Cancer Chemother Pharmacol. 2007, 59 (2): 235-249. 10.1007/s00280-006-0262-1CrossRefPubMed
2.
Tan M, Yu D: Molecular mechanisms of erbB2-mediated breast cancer chemoresistance. Adv Exp Med Biol. 2007, 608: 119-129. full_textCrossRefPubMed
3.
Frankel Andrea, Buckman Robert, Kerbel Robert: Abrogation of Taxol- induced G2-M Arrest and Apoptosis in Human Ovarian Cancer Cells Grown as Multicellular Tumor Spheroids. Cancer Res. 1997, 57: 2388-2293.PubMed
4.
Chen LP, Cai SM, Fan JX, Li ZT: PEBA Regimen (Cisplatin, Etoposide, Bleomycin, and Adriamycin) in the Treatment of Drug-Resistant Choriocarcinoma. Gynecologic Oncology. 2002, 56 (2): 231-234.
5.
Donnenberg Vera, Donnenberg Albert: Multiple Drug Resistance in Cancer Revisited: The Cancer Stem Cell Hypothesis. J Clin Pharmacol. 2005, 45: 872-877. 10.1177/0091270005276905CrossRefPubMed
6.
Gottesman MM, Pastan I: Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu Rev Biochem. 1993, 62: 385-427. 10.1146/annurev.bi.62.070193.002125CrossRefPubMed
7.
Kavallaris M, Kuo DY, Burkhart CA, Regl DL, Norris MD, Haber M, Horwitz SB: Taxol-resistant epithelial ovarian tumors are associated with altered expression of specific beta-tubulin isotypes. J Clin Invest. 1997, 100 (5): 1282-1293. 10.1172/JCI119642PubMedCentralCrossRefPubMed
8.
Panda D, Miller HP, Banerjee A, Ludueña RF, Wilson L: Microtubule dynamics in vitro are regulated by the tubulin isotype composition. Proc Natl Acad Sci USA. 1994, 91 (24): 11358-11362. 10.1073/pnas.91.24.11358PubMedCentralCrossRefPubMed
9.
Martello LA, Verdier-Pinard P, Shen HJ, He L, Torres K, Orr GA, Horwitz SB: Elevated levels of microtubule destabilizing factors in a Taxol-resistant/dependent A549 cell line with an alpha-tubulin mutation. Cancer Res. 2003, 63 (6): 1207-1213.PubMed
10.
Gonçalves A, Braguer D, Kamath K, Martello L, Briand C, Horwitz S, Wilson L, Jordan MA: Resistance to Taxol in lung cancer cells associated with increased microtubule dynamics. Proc Natl Acad Sci. 2001, 98: 11737-11741. 10.1073/pnas.191388598PubMedCentralCrossRefPubMed
11.
Tan M, Jing T, Lan KH, Neal CL, Li P, Lee S, Fang D, Nagata Y, Liu J, Arlinghaus R, Hung MC, Yu D: Phosphorylation on tyrosine-15 of p34(Cdc2) by ErbB2 inhibits p34(Cdc2) activation and is involved in resistance to taxol-induced apoptosis. Mol Cell. 2002, 9: 993-1004. 10.1016/S1097-2765(02)00510-5CrossRefPubMed
12.
Lu J, Tan M, Huang WC, Li P, Guo H, Tseng LM, Su XH, Yang WT, Treekitkarnmongkol W, Andreeff M, Symmans F, Yu D: Mitotic deregulation by survivin in ErbB2-overexpressing breast cancer cells contributes to Taxol resistance. Clin Cancer Res. 2009, 15 (4): 1326-1334. 10.1158/1078-0432.CCR-08-0954PubMedCentralCrossRefPubMed
13.
Warburg O: On respiratory impairment in cancer cells. Science. 1956, 124: 269-270.PubMed
14.
Kim JW, Dang CV: Cancer's molecular sweet tooth and the Warburg effect. Cancer Res. 2006, 66: 8927-8930. 10.1158/0008-5472.CAN-06-1501CrossRefPubMed
15.
Chen Z, Lu W, Garcia-Prieto C, Huang P: The Warburg effect and its cancer therapeutic implications. J Bioenerg Biomembr. 2007, 39 (3): 267-274. 10.1007/s10863-007-9086-xCrossRefPubMed
16.
Fantin VR, St-Pierre J, Leder P: Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance. Cancer Cell. 2006, 9: 425-434. 10.1016/j.ccr.2006.04.023CrossRefPubMed
17.
Dang CV, Semenza GL: Oncogenic alterations of metabolism. Trends Biochem Sci. 1999, 24: 68-72. 10.1016/S0968-0004(98)01344-9CrossRefPubMed
18.
Zhao YH, Zhou M, Liu H, Ding Y, Khong HT, Yu DH, Fodstad O, Tan M: Upregulation of lactate dehydrogenase A by ErbB2 through heat shock factor 1 promotes breast cancer cell glycolysis and growth. Oncogene. 2009, 28: 3689-3701. 10.1038/onc.2009.229CrossRefPubMed
19.
Kaufmann SH, Desnoyers S, Ottaviano Y, Davidson NE, Poirier GG: Specific proteolytic cleavage of poly(ADP-ribose) polymerase: an early marker of chemotherapy-induced apoptosis. Cancer Res. 1993, 53 (17): 3976-3985.PubMed
20.
Boulares AH, Yakovlev AG, Ivanova V, Stoica BA, Wang G, Iyer S, Smulson M: Role of poly(ADP-ribose) polymerase (PARP) cleavage in apoptosis. Caspase 3-resistant PARP mutant increases rates of apoptosis in transfected cells. J Biol Chem. 1999, 274 (33): 22932-22940. 10.1074/jbc.274.33.22932CrossRefPubMed
21.
Chang GG, Huang SM, Chiou SH: Kinetic mechanism of the endogenous lactate dehydrogenase activity of duck epsilon-crystallin. Arch Biochem Biophys. 1991, 284 (2): 285-291. 10.1016/0003-9861(91)90297-VCrossRefPubMed
22.
DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB: The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab. 2008, 7: 11-20. 10.1016/j.cmet.2007.10.002CrossRefPubMed
23.
Kroemer G, Pouyssegur J: Tumor cell metabolism: cancer's Achilles' heel. Cancer Cell. 2008, 13: 472-482. 10.1016/j.ccr.2008.05.005CrossRefPubMed
24.
Gorlach A, Acker H: pO2- and pH-gradients in multicellular spheroids and their relationship to cellular metabolism and radiation sensitivity of malignant human tumor cells. Biochim Biophys Acta. 1994, 1227: 105-112.CrossRefPubMed
25.
Xie H, Valera VA, Merino MJ, Amato AM, Signoretti S, Linehan WM, Sukhatme VP, Seth P: LDH-A inhibition, a therapeutic strategy for treatment of hereditary leiomyomatosis and renal cell cancer. Molecular Cancer Therapeutics. 2009, 8 (3): 626-635. 10.1158/1535-7163.MCT-08-1049PubMedCentralCrossRefPubMed
26.
Vaughn Allyson, Deshmukh Mohanish: Glucose metabolism inhibits apoptosis in neurons and cancer cells by redox inactivation of cytochrome c. Nat Cell Biol. 2008, 10 (12): 1477-1483. 10.1038/ncb1807PubMedCentralCrossRefPubMed
27.
Basu A, DuBois G, Haldar S: Posttranslational modifications of Bcl2 family members--a potential therapeutic target for human malignancy. Front Biosci. 2006, 11: 1508-1521. 10.2741/1900CrossRefPubMed
28.
Fisher DE: Apoptosis in cancer therapy: crossing the threshold. Cell. 1994, 78: 539-42. 10.1016/0092-8674(94)90518-5CrossRefPubMed
29.
Thornburg JM, Nelson KK, Clem BF, Lane AN, Arumugam S, Simmons A, Eaton JW, Telang S, Chesney J: Targeting aspartate aminotransferase in breast cancer. Breast Cancer Res. 2008, 10 (5): R84- 10.1186/bcr2154PubMedCentralCrossRefPubMed
30.
Sellappan S, Grijalva R, Zhou X, Yang W, Eli MB, Mills GB, Yu D: Lineage infidelity of MDA-MB-435 cells: expression of melanocyte proteins in a breast cancer cell line. Cancer Res. 2004, 64: 3479-3485. 10.1158/0008-5472.CAN-3299-2CrossRefPubMed
31.
Welch DR: Technical considerations for studying cancer metastasis in vivo. Clin Exp Metastasis. 1997, 15: 272-306. 10.1023/A:1018477516367CrossRefPubMed
32.
Chambers AF: MDA-MB-435 and M14 cell lines: identical but not M14 melanoma?. Cancer Res. 2009, 69 (13): 5292-5293. 10.1158/0008-5472.CAN-09-1528CrossRefPubMed
Metadata
Title
Warburg effect in chemosensitivity: Targeting lactate dehydrogenase-A re-sensitizes Taxol-resistant cancer cells to Taxol
Authors
Ming Zhou
Yuhua Zhao
Yan Ding
Hao Liu
Zixing Liu
Oystein Fodstad
Adam I Riker
Sushama Kamarajugadda
Jianrong Lu
Laurie B Owen
Susan P Ledoux
Ming Tan
Publication date
01-12-2010
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2010
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/1476-4598-9-33

Other articles of this Issue 1/2010

Molecular Cancer 1/2010 Go to the issue

Research

IGFBP-rP1, a potential molecule associated with colon cancer differentiation

Research

Withanolide D induces apoptosis in leukemia by targeting the activation of neutral sphingomyelinase-ceramide cascade mediated by synergistic activation of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase

Research

Cathepsin B inhibition interferes with metastatic potential of human melanoma: an in vitro and in vivo study

Research

Epstein-Barr virus-encoded EBNA1 inhibits the canonical NF-κB pathway in carcinoma cells by inhibiting IKK phosphorylation

Research

The anti-aging gene KLOTHO is a novel target for epigenetic silencing in human cervical carcinoma

Research

Elevated level of anterior gradient-2 in pancreatic juice from patients with pre-malignant pancreatic neoplasia
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits