Enhanced heme function and mitochondrial respiration promote the progression of lung cancer cells

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Enhanced heme function and mitochondrial respiration promote the progression of lung cancer cells

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Title: Enhanced heme function and mitochondrial respiration promote the progression of lung cancer cells
Author(s):
Hooda, Jagmohan;
Cadinu, Daniela;
Alam, Md Maksudul;
Shah, Ajit;
Cao, Thai M.;
Sullivan, Laura A.;
Brekken, Rolf;
Zhang, Li (UT Dallas)
Format: Text
Item Type: Article
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Abstract: Lung cancer is the leading cause of cancer-related mortality, and about 85% of the cases are non-small-cell lung cancer (NSCLC). Importantly, recent advance in cancer research suggests that altering cancer cell bioenergetics can provide an effective way to target such advanced cancer cells that have acquired mutations in multiple cellular regulators. This study aims to identify bioenergetic alterations in lung cancer cells by directly measuring and comparing key metabolic activities in a pair of cell lines representing normal and NSCLC cells developed from the same patient. We found that the rates of oxygen consumption and heme biosynthesis were intensified in NSCLC cells. Additionally, the NSCLC cells exhibited substantially increased levels in an array of proteins promoting heme synthesis, uptake and function. These proteins include the rate-limiting heme biosynthetic enzyme ALAS, transporter proteins HRG1 and HCP1 that are involved in heme uptake, and various types of oxygen-utilizing hemoproteins such as cytoglobin and cytochromes. Several types of human tumor xenografts also displayed increased levels of such proteins. Furthermore, we found that lowering heme biosynthesis and uptake, like lowering mitochondrial respiration, effectively reduced oxygen consumption, cancer cell proliferation, migration and colony formation. In contrast, lowering heme degradation does not have an effect on lung cancer cells. These results show that increased heme flux and function are a key feature of NSCLC cells. Further, increased generation and supply of heme and oxygen-utilizing hemoproteins in cancer cells will lead to intensified oxygen consumption and cellular energy production by mitochondrial respiration, which would fuel cancer cell proliferation and progression. The results show that inhibiting heme and respiratory function can effectively arrest the progression of lung cancer cells. Hence, understanding heme function can positively impact on research in lung cancer biology and therapeutics.
Alternative Title: PLOS One
ISSN: 1932-6203
Persistent Link: http://hdl.handle.net/10735.1/3729
http://dx.doi.org/10.1371/journal.pone.0063402
Terms of Use: ©2013 The Authors. "This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited."
Sponsors: This work was supported by the Cecil H. and Ida Green funds (LZ) and the NCI SPORE P50CA70907 grant (RB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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