Mitochondria as new therapeutic targets for eradicating cancer stem cells: Quantitative proteomics and functional validation via MCT1/2 inhibition
Here, we used quantitative proteomics analysis to identify novel therapeutic targets in cancer stem cells and/or progenitor cells. For this purpose, mammospheres from two ER-positive breast cancer cell lines (MCF7 and T47D) were grown in suspension using low-attachment plates and directly compared t...
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| Vydáno v: | Oncotarget Ročník 5; číslo 22; s. 11029 |
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| Hlavní autoři: | , , , , , |
| Médium: | Journal Article |
| Jazyk: | angličtina |
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United States
30.11.2014
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| ISSN: | 1949-2553, 1949-2553 |
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| Abstract | Here, we used quantitative proteomics analysis to identify novel therapeutic targets in cancer stem cells and/or progenitor cells. For this purpose, mammospheres from two ER-positive breast cancer cell lines (MCF7 and T47D) were grown in suspension using low-attachment plates and directly compared to attached monolayer cells grown in parallel. This allowed us to identify a subset of proteins that were selectively over-expressed in mammospheres, relative to epithelial monolayers. We focused on mitochondrial proteins, as they appeared to be highly upregulated in both MCF7 and T47D mammospheres. Key mitochondrial-related enzymes involved in beta-oxidation and ketone metabolism were significantly upregulated in mammospheres, as well as proteins involved in mitochondrial biogenesis, and specific protein inhibitors of autophagy/mitophagy. Overall, we identified >40 "metabolic targets" that were commonly upregulated in both MCF7 and T47D mammospheres. Most of these "metabolic targets" were also transcriptionally upregulated in human breast cancer cells in vivo, validating their clinical relevance. Based on this analysis, we propose that increased mitochondrial biogenesis and decreased mitochondrial degradation could provide a novel mechanism for the accumulation of mitochondrial mass in cancer stem cells. To functionally validate our observations, we utilized a specific MCT1/2 inhibitor (AR-C155858), which blocks the cellular uptake of two types of mitochondrial fuels, namely ketone bodies and L-lactate. Our results indicate that inhibition of MCT1/2 function effectively reduces mammosphere formation, with an IC-50 of ~1 µM, in both ER-positive and ER-negative breast cancer cell lines. Very similar results were obtained with oligomycin A, an inhibitor of the mitochondrial ATP synthase. Thus, the proliferative clonal expansion of cancer stem cells appears to require oxidative mitochondrial metabolism, related to the re-use of monocarboxylic acids, such as ketones or L-lactate. Our findings have important clinical implications for exploiting mitochondrial metabolism to eradicate cancer stem cells and to prevent recurrence, metastasis and drug resistance in cancer patients. Importantly, a related MCT1/2 inhibitor (AZD3965) is currently in phase I clinical trials in patients with advanced cancers: http://clinicaltrials.gov/show/NCT01791595. |
|---|---|
| AbstractList | Here, we used quantitative proteomics analysis to identify novel therapeutic targets in cancer stem cells and/or progenitor cells. For this purpose, mammospheres from two ER-positive breast cancer cell lines (MCF7 and T47D) were grown in suspension using low-attachment plates and directly compared to attached monolayer cells grown in parallel. This allowed us to identify a subset of proteins that were selectively over-expressed in mammospheres, relative to epithelial monolayers. We focused on mitochondrial proteins, as they appeared to be highly upregulated in both MCF7 and T47D mammospheres. Key mitochondrial-related enzymes involved in beta-oxidation and ketone metabolism were significantly upregulated in mammospheres, as well as proteins involved in mitochondrial biogenesis, and specific protein inhibitors of autophagy/mitophagy. Overall, we identified >40 "metabolic targets" that were commonly upregulated in both MCF7 and T47D mammospheres. Most of these "metabolic targets" were also transcriptionally upregulated in human breast cancer cells in vivo, validating their clinical relevance. Based on this analysis, we propose that increased mitochondrial biogenesis and decreased mitochondrial degradation could provide a novel mechanism for the accumulation of mitochondrial mass in cancer stem cells. To functionally validate our observations, we utilized a specific MCT1/2 inhibitor (AR-C155858), which blocks the cellular uptake of two types of mitochondrial fuels, namely ketone bodies and L-lactate. Our results indicate that inhibition of MCT1/2 function effectively reduces mammosphere formation, with an IC-50 of ~1 µM, in both ER-positive and ER-negative breast cancer cell lines. Very similar results were obtained with oligomycin A, an inhibitor of the mitochondrial ATP synthase. Thus, the proliferative clonal expansion of cancer stem cells appears to require oxidative mitochondrial metabolism, related to the re-use of monocarboxylic acids, such as ketones or L-lactate. Our findings have important clinical implications for exploiting mitochondrial metabolism to eradicate cancer stem cells and to prevent recurrence, metastasis and drug resistance in cancer patients. Importantly, a related MCT1/2 inhibitor (AZD3965) is currently in phase I clinical trials in patients with advanced cancers: http://clinicaltrials.gov/show/NCT01791595.Here, we used quantitative proteomics analysis to identify novel therapeutic targets in cancer stem cells and/or progenitor cells. For this purpose, mammospheres from two ER-positive breast cancer cell lines (MCF7 and T47D) were grown in suspension using low-attachment plates and directly compared to attached monolayer cells grown in parallel. This allowed us to identify a subset of proteins that were selectively over-expressed in mammospheres, relative to epithelial monolayers. We focused on mitochondrial proteins, as they appeared to be highly upregulated in both MCF7 and T47D mammospheres. Key mitochondrial-related enzymes involved in beta-oxidation and ketone metabolism were significantly upregulated in mammospheres, as well as proteins involved in mitochondrial biogenesis, and specific protein inhibitors of autophagy/mitophagy. Overall, we identified >40 "metabolic targets" that were commonly upregulated in both MCF7 and T47D mammospheres. Most of these "metabolic targets" were also transcriptionally upregulated in human breast cancer cells in vivo, validating their clinical relevance. Based on this analysis, we propose that increased mitochondrial biogenesis and decreased mitochondrial degradation could provide a novel mechanism for the accumulation of mitochondrial mass in cancer stem cells. To functionally validate our observations, we utilized a specific MCT1/2 inhibitor (AR-C155858), which blocks the cellular uptake of two types of mitochondrial fuels, namely ketone bodies and L-lactate. Our results indicate that inhibition of MCT1/2 function effectively reduces mammosphere formation, with an IC-50 of ~1 µM, in both ER-positive and ER-negative breast cancer cell lines. Very similar results were obtained with oligomycin A, an inhibitor of the mitochondrial ATP synthase. Thus, the proliferative clonal expansion of cancer stem cells appears to require oxidative mitochondrial metabolism, related to the re-use of monocarboxylic acids, such as ketones or L-lactate. Our findings have important clinical implications for exploiting mitochondrial metabolism to eradicate cancer stem cells and to prevent recurrence, metastasis and drug resistance in cancer patients. Importantly, a related MCT1/2 inhibitor (AZD3965) is currently in phase I clinical trials in patients with advanced cancers: http://clinicaltrials.gov/show/NCT01791595. Here, we used quantitative proteomics analysis to identify novel therapeutic targets in cancer stem cells and/or progenitor cells. For this purpose, mammospheres from two ER-positive breast cancer cell lines (MCF7 and T47D) were grown in suspension using low-attachment plates and directly compared to attached monolayer cells grown in parallel. This allowed us to identify a subset of proteins that were selectively over-expressed in mammospheres, relative to epithelial monolayers. We focused on mitochondrial proteins, as they appeared to be highly upregulated in both MCF7 and T47D mammospheres. Key mitochondrial-related enzymes involved in beta-oxidation and ketone metabolism were significantly upregulated in mammospheres, as well as proteins involved in mitochondrial biogenesis, and specific protein inhibitors of autophagy/mitophagy. Overall, we identified >40 "metabolic targets" that were commonly upregulated in both MCF7 and T47D mammospheres. Most of these "metabolic targets" were also transcriptionally upregulated in human breast cancer cells in vivo, validating their clinical relevance. Based on this analysis, we propose that increased mitochondrial biogenesis and decreased mitochondrial degradation could provide a novel mechanism for the accumulation of mitochondrial mass in cancer stem cells. To functionally validate our observations, we utilized a specific MCT1/2 inhibitor (AR-C155858), which blocks the cellular uptake of two types of mitochondrial fuels, namely ketone bodies and L-lactate. Our results indicate that inhibition of MCT1/2 function effectively reduces mammosphere formation, with an IC-50 of ~1 µM, in both ER-positive and ER-negative breast cancer cell lines. Very similar results were obtained with oligomycin A, an inhibitor of the mitochondrial ATP synthase. Thus, the proliferative clonal expansion of cancer stem cells appears to require oxidative mitochondrial metabolism, related to the re-use of monocarboxylic acids, such as ketones or L-lactate. Our findings have important clinical implications for exploiting mitochondrial metabolism to eradicate cancer stem cells and to prevent recurrence, metastasis and drug resistance in cancer patients. Importantly, a related MCT1/2 inhibitor (AZD3965) is currently in phase I clinical trials in patients with advanced cancers: http://clinicaltrials.gov/show/NCT01791595. |
| Author | Hulit, James Lisanti, Michael P Lamb, Rebecca Smith, Duncan L Harrison, Hannah Sotgia, Federica |
| Author_xml | – sequence: 1 givenname: Rebecca surname: Lamb fullname: Lamb, Rebecca organization: The Manchester Centre for Cellular Metabolism (MCCM), Institute of Cancer Sciences, University of Manchester. The Breakthrough Breast Cancer Research Unit, Institute of Cancer Sciences, University of Manchester – sequence: 2 givenname: Hannah surname: Harrison fullname: Harrison, Hannah organization: The Manchester Centre for Cellular Metabolism (MCCM), Institute of Cancer Sciences, University of Manchester. The Breakthrough Breast Cancer Research Unit, Institute of Cancer Sciences, University of Manchester – sequence: 3 givenname: James surname: Hulit fullname: Hulit, James organization: The Manchester Centre for Cellular Metabolism (MCCM), Institute of Cancer Sciences, University of Manchester. The Breakthrough Breast Cancer Research Unit, Institute of Cancer Sciences, University of Manchester – sequence: 4 givenname: Duncan L surname: Smith fullname: Smith, Duncan L organization: The Cancer Research UK Manchester Institute, University of Manchester – sequence: 5 givenname: Michael P surname: Lisanti fullname: Lisanti, Michael P organization: The Manchester Centre for Cellular Metabolism (MCCM), Institute of Cancer Sciences, University of Manchester. The Breakthrough Breast Cancer Research Unit, Institute of Cancer Sciences, University of Manchester – sequence: 6 givenname: Federica surname: Sotgia fullname: Sotgia, Federica organization: The Manchester Centre for Cellular Metabolism (MCCM), Institute of Cancer Sciences, University of Manchester. The Breakthrough Breast Cancer Research Unit, Institute of Cancer Sciences, University of Manchester |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/25415228$$D View this record in MEDLINE/PubMed |
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| References | 24185040 - Oncotarget. 2013 Nov;4(11):1948-62 25149175 - Oncotarget. 2014 Aug 30;5(16):6816-31 24699023 - J Stem Cells. 2013;8(3-4):135-49 22665270 - J Mammary Gland Biol Neoplasia. 2012 Jun;17(2):111-7 24934860 - Aging (Albany NY). 2014 Jun;6(6):481-95 24672058 - Mol Cancer Ther. 2014 Jun;13(6):1410-8 25315652 - Mitochondrion. 2015 Jan;20:43-51 16377171 - Curr Opin Genet Dev. 2006 Feb;16(1):60-4 23945201 - Aging (Albany NY). 2013 Aug;5(8):588-9 18373191 - Breast Cancer Res Treat. 2009 Mar;114(1):47-62 19545218 - Expert Opin Biol Ther. 2009 Aug;9(8):1005-16 24994116 - Oncotarget. 2014 Jun 30;5(12):3970-82 20587011 - Stem Cell Res Ther. 2010;1(2):13 19929853 - Biochem J. 2010 Feb 1;425(3):523-30 20695846 - Biochem J. 2010 Oct 15;431(2):217-25 23303788 - Nucleic Acids Res. 2013 Feb 1;41(4):2255-66 23603840 - Oncotarget. 2013 Apr;4(4):584-99 21512313 - Cell Cycle. 2011 Apr 15;10(8):1271-86 21606482 - Blood. 2011 Jul 21;118(3):638-49 23574725 - Cell Cycle. 2013 May 1;12(9):1371-84 22565037 - Oncotarget. 2012 Apr;3(4):395-8 24161908 - Oncotarget. 2013 Nov;4(11):1986-98 19812375 - FASEB J. 2010 Feb;24(2):464-78 22201672 - Oncotarget. 2011 Dec;2(12):1145-54 |
| References_xml | – reference: 24161908 - Oncotarget. 2013 Nov;4(11):1986-98 – reference: 24994116 - Oncotarget. 2014 Jun 30;5(12):3970-82 – reference: 20587011 - Stem Cell Res Ther. 2010;1(2):13 – reference: 19545218 - Expert Opin Biol Ther. 2009 Aug;9(8):1005-16 – reference: 21512313 - Cell Cycle. 2011 Apr 15;10(8):1271-86 – reference: 22201672 - Oncotarget. 2011 Dec;2(12):1145-54 – reference: 24934860 - Aging (Albany NY). 2014 Jun;6(6):481-95 – reference: 21606482 - Blood. 2011 Jul 21;118(3):638-49 – reference: 22665270 - J Mammary Gland Biol Neoplasia. 2012 Jun;17(2):111-7 – reference: 18373191 - Breast Cancer Res Treat. 2009 Mar;114(1):47-62 – reference: 20695846 - Biochem J. 2010 Oct 15;431(2):217-25 – reference: 23574725 - Cell Cycle. 2013 May 1;12(9):1371-84 – reference: 24699023 - J Stem Cells. 2013;8(3-4):135-49 – reference: 23945201 - Aging (Albany NY). 2013 Aug;5(8):588-9 – reference: 23603840 - Oncotarget. 2013 Apr;4(4):584-99 – reference: 25149175 - Oncotarget. 2014 Aug 30;5(16):6816-31 – reference: 19812375 - FASEB J. 2010 Feb;24(2):464-78 – reference: 16377171 - Curr Opin Genet Dev. 2006 Feb;16(1):60-4 – reference: 23303788 - Nucleic Acids Res. 2013 Feb 1;41(4):2255-66 – reference: 25315652 - Mitochondrion. 2015 Jan;20:43-51 – reference: 22565037 - Oncotarget. 2012 Apr;3(4):395-8 – reference: 24672058 - Mol Cancer Ther. 2014 Jun;13(6):1410-8 – reference: 19929853 - Biochem J. 2010 Feb 1;425(3):523-30 – reference: 24185040 - Oncotarget. 2013 Nov;4(11):1948-62 |
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| SubjectTerms | Breast Neoplasms - drug therapy Breast Neoplasms - genetics Breast Neoplasms - metabolism Breast Neoplasms - pathology Cell Line, Tumor Female Humans MCF-7 Cells Mitochondria - drug effects Mitochondria - metabolism Mitochondrial Proteins - antagonists & inhibitors Mitochondrial Proteins - genetics Mitochondrial Proteins - metabolism Molecular Targeted Therapy Monocarboxylic Acid Transporters - antagonists & inhibitors Neoplastic Stem Cells - drug effects Neoplastic Stem Cells - metabolism Neoplastic Stem Cells - pathology Proteomics - methods Symporters - antagonists & inhibitors Thiophenes - pharmacology Uracil - analogs & derivatives Uracil - pharmacology |
| Title | Mitochondria as new therapeutic targets for eradicating cancer stem cells: Quantitative proteomics and functional validation via MCT1/2 inhibition |
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