Glioblastoma multiforme (GBM) is the most common primary intracranial neoplasm and its almost uniform lethality. Temozolomide (TMZ) is the standard of care for the treatment of GBM patients showing small but significant increases in median survival of 4 weeks. However, acquisition of TMZ-chemoresistance is one of the major obstacles to efficient therapy for GBM patients. Despite aggressive treatment approaches, recurrence occurs in 90% of GBM patients. One cause of this poor outcome is development of a drug resistance. The mechanism underlying drug resistance is still not well understood thus challenging the development of more effective strategies and/or novel therapeutics to overcome this resistance. Mitochondria (mt) are at the cross road of energy production and apoptotic pathways. Their role in cancer etiology is significant;however, information regarding mt function and chemoresistance remains poorly defined. The enzyme cytochrome c oxidase (CcO) (EC 1.9.3.1) is a large mt transmembrane protein complex. It is the last enzyme in the respiratory electron transport chain (ETC) that transfers electrons from cytochrome c (Cyt c) to molecular oxygen (O2). Cyt c and O2 are the main substrates of CcO and both are directly involved in the intrinsic mt apoptotic pathway and hypoxia. While most of the studies to date have focus on CcO involvement in mt oxidative phosphorylation, any casual relation between CcO activity, CcO-nuclear-encoded subunits and the development of resistance to apoptosis in GBM is unclear and is the subject of this proposal. Recently, we demonstrated that acquisition of TMZ-resistance correlates with a significant increase of CcO activity in culture glioma cells as well a paired primary-recurrent GBM patient biopsies. The discovery of similar alterations in CcO activity between primary and recurrent human GBM specimens in patients subjected to TMZ-radiotherapy emphasizes the clinical significance of the findings and the primary role of TMZ in mediating these effects. Moreover, pharmacological or genetic inhibition of CcO in TMZ-resistant cells restores TMZ-induced apoptosis. The goal of this proposal is to test the hypothesis that CcO subunit 4 isoform 1 (COX4-1) drives chemoresistance in GBM through changes in 1) CcO assembly/ function and 2) cellular redox homeostasis by achieving three specific aims: We will determine whether: (1) Determine the effects of COX4-1 and 2 isoforms on the assembly/ function of CcO and on resistance to TMZ, (2) Determine the effects of COX4-1 and 2 isoforms on cellular redox status and on resistance to TMZ and 3) Determine the activity of CcO and expression of COX4-1 and 2 isoforms in brain tumor patient biopsies. Upon completion of this research, we expect to have developed a substantial base of knowledge on the role of CcO in the apoptotic response to TMZ. Our long term goal is to apply this information for the development of CcO-based therapies as well as for the development of prognostic markers for chemoresistance and GBM recurrence.

Public Health Relevance

It is well-established that malignant gliomas are generally very resistant to chemotherapeutic modalities with minimal improvement in patient progression-free or overall survivals following aggressive regimens. Furthermore, cells that escape radio- and chemotherapy-induced cell death eventually reenter the cell cycle and contribute to local tumor recurrence in 90% of cases. Unfortunately, after recurrency, therapeutic options are only palliative and overall extremely expensive. Hence, there is a dire need to target the cells that evade current treatments. The role of Cytochrome c oxidase (CcO) in the acquisition of resistant to chemotherapy in gliomas is a novel hypothesis and might highlight: 1) the importance of CcO inhibitors-based drug therapies;2) the importance of CcO expression levels as determinants of treatment prognosis of gliomas. In this respect, CcO and mitochondrial metabolism are potentially attractive therapeutic targets in the treatment of TMZ-resistant gliomas

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA160821-03
Application #
8643090
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Forry, Suzanne L
Project Start
2012-05-01
Project End
2017-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
3
Fiscal Year
2014
Total Cost
$294,868
Indirect Cost
$93,593
Name
University of Alabama Birmingham
Department
Surgery
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Bernal Rubio, Yeni L; González-Reymúndez, Agustin; Wu, Kuan-Han H et al. (2018) Whole-Genome Multi-omic Study of Survival in Patients with Glioblastoma Multiforme. G3 (Bethesda) 8:3627-3636
Libby, Catherine J; Tran, Anh Nhat; Scott, Sarah E et al. (2018) The pro-tumorigenic effects of metabolic alterations in glioblastoma including brain tumor initiating cells. Biochim Biophys Acta Rev Cancer 1869:175-188
Oliva, Claudia R; Halloran, Brian; Hjelmeland, Anita B et al. (2018) IGFBP6 controls the expansion of chemoresistant glioblastoma through paracrine IGF2/IGF-1R signaling. Cell Commun Signal 16:61
Oliva, Claudia R; Zhang, Wei; Langford, Cathy et al. (2017) Repositioning chlorpromazine for treating chemoresistant glioma through the inhibition of cytochrome c oxidase bearing the COX4-1 regulatory subunit. Oncotarget 8:37568-37583
Boyd, Nathaniel H; Walker, Kiera; Fried, Joshua et al. (2017) Addition of carbonic anhydrase 9 inhibitor SLC-0111 to temozolomide treatment delays glioblastoma growth in vivo. JCI Insight 2:
King, Adrienne L; Mantena, Sudheer K; Andringa, Kelly K et al. (2016) The methyl donor S-adenosylmethionine prevents liver hypoxia and dysregulation of mitochondrial bioenergetic function in a rat model of alcohol-induced fatty liver disease. Redox Biol 9:188-197
Oliva, Claudia R; Markert, Tahireh; Ross, Larry J et al. (2016) Identification of Small Molecule Inhibitors of Human Cytochrome c Oxidase That Target Chemoresistant Glioma Cells. J Biol Chem 291:24188-24199
Oliva, Claudia R; Markert, Tahireh; Gillespie, G Yancey et al. (2015) Nuclear-encoded cytochrome c oxidase subunit 4 regulates BMI1 expression and determines proliferative capacity of high-grade gliomas. Oncotarget 6:4330-44
King, Adrienne L; Swain, Telisha M; Mao, Zhengkuan et al. (2014) Involvement of the mitochondrial permeability transition pore in chronic ethanol-mediated liver injury in mice. Am J Physiol Gastrointest Liver Physiol 306:G265-77
Griguer, Corinne E; Cantor, Alan B; Fathallah-Shaykh, Hassan M et al. (2013) Prognostic relevance of cytochrome C oxidase in primary glioblastoma multiforme. PLoS One 8:e61035

Showing the most recent 10 out of 13 publications