TNF-α differentially modulates subunit levels of respiratory electron transport complexes of ER/PR +ve/−ve breast cancer cells to regulate mitochondrial complex ... View Full Text


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Article Info

DATE

2021-04-29

AUTHORS

Anjali Shinde, Hyeryeon Jung, Hayun Lee, Kritarth Singh, Milton Roy, Dhruv Gohel, Han Byeol Kim, Minal Mane, Hitesh Vasiyani, Fatema Currim, Yu Ri Seo, Seojin Yang, Ara Cho, Eugene C. Yi, Rajesh Singh

ABSTRACT

BackgroundTumor necrosis factor-α (TNF-α) is an immunostimulatory cytokine that is consistently high in the breast tumor microenvironment (TME); however, its differential role in mitochondrial functions and cell survival in ER/PR +ve and ER/PR −ve breast cancer cells is not well understood.MethodsIn the current study, we investigated TNF-α modulated mitochondrial proteome using high-resolution mass spectrometry and identified the differentially expressed proteins in two different breast cancer cell lines, ER/PR positive cell line; luminal, MCF-7 and ER/PR negative cell line; basal-like, MDA-MB-231 and explored its implication in regulating the tumorigenic potential of breast cancer cells. We also compared the activity of mitochondrial complexes, ATP, and ROS levels between MCF-7 and MDA-MB-231 in the presence of TNF-α. We used Tumor Immune Estimation Resource (TIMER) webserver to analyze the correlation between TNF-α and mitochondrial proteins in basal and luminal breast cancer patients. Kaplan-Meier method was used to analyze the correlation between mitochondrial protein expression and survival of breast cancer patients.ResultsThe proteome analysis revealed that TNF-α differentially altered the level of critical proteins of mitochondrial respiratory chain complexes both in MCF-7 and MDA-MB-231, which correlated with differential assembly and activity of mitochondrial ETC complexes. The inhibition of the glycolytic pathway in the presence of TNF-α showed that glycolysis is indispensable for the proliferation and clonogenic ability of MDA-MB-231 cells (ER/PR −ve) as compared to MCF-7 cells (ER/PR +ve). The TIMER database showed a negative correlation between the expressions of TNF-α and key regulators of mitochondrial OXPHOS complexes in basal breast vs lobular carcinoma. Conversely, patient survival analysis showed an improved relapse-free survival with increased expression of identified proteins of ETC complexes and survival of the breast cancer patients.ConclusionThe evidence presented in our study convincingly demonstrates that TNF-α regulates the survival and proliferation of aggressive tumor cells by modulating the levels of critical assembly factors and subunits involved in mitochondrial respiratory chain supercomplexes organization and function. This favors the rewiring of mitochondrial metabolism towards anaplerosis to support the survival and proliferation of breast cancer cells. Collectively, the results strongly suggest that TNF-α differentially regulates metabolic adaptation in ER/PR +ve (MCF-7) and ER/PR −ve (MDA-MB-231) cells by modulating the mitochondrial supercomplex assembly and activity. More... »

PAGES

19

Identifiers

URI

http://scigraph.springernature.com/pub.10.1186/s40170-021-00254-9

DOI

http://dx.doi.org/10.1186/s40170-021-00254-9

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1137601379

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/33926547


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11 schema:description BackgroundTumor necrosis factor-α (TNF-α) is an immunostimulatory cytokine that is consistently high in the breast tumor microenvironment (TME); however, its differential role in mitochondrial functions and cell survival in ER/PR +ve and ER/PR −ve breast cancer cells is not well understood.MethodsIn the current study, we investigated TNF-α modulated mitochondrial proteome using high-resolution mass spectrometry and identified the differentially expressed proteins in two different breast cancer cell lines, ER/PR positive cell line; luminal, MCF-7 and ER/PR negative cell line; basal-like, MDA-MB-231 and explored its implication in regulating the tumorigenic potential of breast cancer cells. We also compared the activity of mitochondrial complexes, ATP, and ROS levels between MCF-7 and MDA-MB-231 in the presence of TNF-α. We used Tumor Immune Estimation Resource (TIMER) webserver to analyze the correlation between TNF-α and mitochondrial proteins in basal and luminal breast cancer patients. Kaplan-Meier method was used to analyze the correlation between mitochondrial protein expression and survival of breast cancer patients.ResultsThe proteome analysis revealed that TNF-α differentially altered the level of critical proteins of mitochondrial respiratory chain complexes both in MCF-7 and MDA-MB-231, which correlated with differential assembly and activity of mitochondrial ETC complexes. The inhibition of the glycolytic pathway in the presence of TNF-α showed that glycolysis is indispensable for the proliferation and clonogenic ability of MDA-MB-231 cells (ER/PR −ve) as compared to MCF-7 cells (ER/PR +ve). The TIMER database showed a negative correlation between the expressions of TNF-α and key regulators of mitochondrial OXPHOS complexes in basal breast vs lobular carcinoma. Conversely, patient survival analysis showed an improved relapse-free survival with increased expression of identified proteins of ETC complexes and survival of the breast cancer patients.ConclusionThe evidence presented in our study convincingly demonstrates that TNF-α regulates the survival and proliferation of aggressive tumor cells by modulating the levels of critical assembly factors and subunits involved in mitochondrial respiratory chain supercomplexes organization and function. This favors the rewiring of mitochondrial metabolism towards anaplerosis to support the survival and proliferation of breast cancer cells. Collectively, the results strongly suggest that TNF-α differentially regulates metabolic adaptation in ER/PR +ve (MCF-7) and ER/PR −ve (MDA-MB-231) cells by modulating the mitochondrial supercomplex assembly and activity.
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17 schema:keywords BackgroundTumor necrosis factor
18 ER/PR
19 ETC complexes
20 Kaplan-Meier method
21 MCF-7
22 MCF-7 cells
23 MDA-MB-231
24 MDA-MB-231 cells
25 MethodsIn
26 OXPHOS complexes
27 PR
28 ROS levels
29 TIMER database
30 TNF
31 VE
32 ability
33 activity
34 adaptation
35 aggressive tumor cells
36 analysis
37 anaplerosis
38 assembly
39 assembly factors
40 breast
41 breast cancer cell lines
42 breast cancer cells
43 breast cancer patients
44 breast tumor microenvironment
45 cancer cell lines
46 cancer cells
47 cancer patients
48 carcinoma
49 cell lines
50 cell survival
51 cells
52 chain
53 chain complexes
54 clonogenic ability
55 complex activity
56 complexes
57 correlation
58 critical proteins
59 current study
60 cytokines
61 database
62 different breast cancer cell lines
63 differential assembly
64 differential roles
65 electron transport complexes
66 evidence
67 expression
68 expression of TNF
69 factors
70 function
71 glycolysis
72 glycolytic pathway
73 high-resolution mass spectrometry
74 immunostimulatory cytokines
75 implications
76 improved relapse-free survival
77 inhibition
78 key regulator
79 levels
80 lines
81 lobular carcinoma
82 luminal breast cancer patients
83 mass spectrometry
84 metabolic adaptation
85 metabolism
86 method
87 microenvironment
88 mitochondrial ETC complexes
89 mitochondrial OXPHOS complexes
90 mitochondrial complex activity
91 mitochondrial complexes
92 mitochondrial function
93 mitochondrial metabolism
94 mitochondrial protein expression
95 mitochondrial proteins
96 mitochondrial proteome
97 mitochondrial respiratory chain
98 mitochondrial respiratory chain complexes
99 mitochondrial supercomplex assembly
100 necrosis factor
101 negative cell lines
102 negative correlation
103 organization
104 pathway
105 patient survival analysis
106 patients
107 positive cell lines
108 potential
109 presence
110 presence of TNF
111 proliferation
112 protein
113 protein expression
114 proteome
115 proteome analysis
116 regulator
117 relapse-free survival
118 respiratory chain
119 respiratory chain complexes
120 respiratory electron transport complexes
121 results
122 rewiring
123 role
124 spectrometry
125 study
126 subunit levels
127 subunits
128 supercomplex assembly
129 survival
130 survival analysis
131 transport complex
132 tumor cells
133 tumor microenvironment
134 tumorigenic potential
135 webserver
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