Mitochondrial Respiration in <i>KRAS</i> and <i>BRAF</i> Mutated Colorectal Tumors and Polyps
This study aimed to characterize the ATP-synthesis by oxidative phosphorylation in colorectal cancer (CRC) and premalignant colon polyps in relation to molecular biomarkers KRAS and BRAF. This prospective study included 48 patients. Resected colorectal polyps and postoperative CRC tissue with adjace...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-03-01
|
| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/12/4/815 |
| _version_ | 1797626431332679680 |
|---|---|
| author | Egle Rebane-Klemm Laura Truu Leenu Reinsalu Marju Puurand Igor Shevchuk Vladimir Chekulayev Natalja Timohhina Kersti Tepp Jelena Bogovskaja Vladimir Afanasjev Külliki Suurmaa Vahur Valvere Tuuli Kaambre |
| author_facet | Egle Rebane-Klemm Laura Truu Leenu Reinsalu Marju Puurand Igor Shevchuk Vladimir Chekulayev Natalja Timohhina Kersti Tepp Jelena Bogovskaja Vladimir Afanasjev Külliki Suurmaa Vahur Valvere Tuuli Kaambre |
| author_sort | Egle Rebane-Klemm |
| collection | DOAJ |
| description | This study aimed to characterize the ATP-synthesis by oxidative phosphorylation in colorectal cancer (CRC) and premalignant colon polyps in relation to molecular biomarkers KRAS and BRAF. This prospective study included 48 patients. Resected colorectal polyps and postoperative CRC tissue with adjacent normal tissue (control) were collected. Patients with polyps and CRC were divided into three molecular groups: <i>KRAS</i> mutated, <i>BRAF</i> mutated and <i>KRAS/BRAF</i> wild-type. Mitochondrial respiration in permeabilized tissue samples was observed using high resolution respirometry. ADP-activated respiration rate (V<sub>max</sub>) and an apparent affinity of mitochondria to ADP, which is related to mitochondrial outer membrane (MOM) permeability, were determined. Clear differences were present between molecular groups. <i>KRAS</i> mutated CRC group had lower V<sub>max</sub> values compared to wild-type; however, the V<sub>max</sub> value was higher than in the control group, while MOM permeability did not change. This suggests that <i>KRAS</i> mutation status might be involved in acquiring oxidative phenotype. <i>KRAS</i> mutated polyps had higher V<sub>max</sub> values and elevated MOM permeability as compared to the control. <i>BRAF</i> mutated CRC and polyps had reduced respiration and altered MOM permeability, indicating a glycolytic phenotype. To conclude, prognostic biomarkers KRAS and BRAF are likely related to the metabolic phenotype in CRC and polyps. Assessment of the tumor mitochondrial ATP synthesis could be a potential component of patient risk stratification. |
| first_indexed | 2024-03-11T10:10:17Z |
| format | Article |
| id | doaj.art-d13bd31f853c496c93ecf688af699a76 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-11T10:10:17Z |
| publishDate | 2020-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-d13bd31f853c496c93ecf688af699a762023-11-16T14:37:04ZengMDPI AGCancers2072-66942020-03-0112481510.3390/cancers12040815Mitochondrial Respiration in <i>KRAS</i> and <i>BRAF</i> Mutated Colorectal Tumors and PolypsEgle Rebane-Klemm0Laura Truu1Leenu Reinsalu2Marju Puurand3Igor Shevchuk4Vladimir Chekulayev5Natalja Timohhina6Kersti Tepp7Jelena Bogovskaja8Vladimir Afanasjev9Külliki Suurmaa10Vahur Valvere11Tuuli Kaambre12Laboratory of Chemical Biology, National Institute of Chemical Physics and Biophysics, Akadeemia tee 23, 12618 Tallinn, EstoniaLaboratory of Chemical Biology, National Institute of Chemical Physics and Biophysics, Akadeemia tee 23, 12618 Tallinn, EstoniaLaboratory of Chemical Biology, National Institute of Chemical Physics and Biophysics, Akadeemia tee 23, 12618 Tallinn, EstoniaLaboratory of Chemical Biology, National Institute of Chemical Physics and Biophysics, Akadeemia tee 23, 12618 Tallinn, EstoniaLaboratory of Chemical Biology, National Institute of Chemical Physics and Biophysics, Akadeemia tee 23, 12618 Tallinn, EstoniaLaboratory of Chemical Biology, National Institute of Chemical Physics and Biophysics, Akadeemia tee 23, 12618 Tallinn, EstoniaLaboratory of Chemical Biology, National Institute of Chemical Physics and Biophysics, Akadeemia tee 23, 12618 Tallinn, EstoniaLaboratory of Chemical Biology, National Institute of Chemical Physics and Biophysics, Akadeemia tee 23, 12618 Tallinn, EstoniaClinic of Diagnostics at the North Estonia Medical Centre, J. Sütiste tee 19, 13419 Tallinn, EstoniaClinic of Surgery at the North Estonia Medical Centre, J. Sütiste tee 19, 13419 Tallinn, EstoniaDepartment of Gastroenterology, the West Tallinn Central Hospital, Paldiski mnt 68, 10617 Tallinn, EstoniaOncology and Haematology Clinic at the North Estonia Medical Centre, J. Sütiste tee 19, 13419 Tallinn, EstoniaLaboratory of Chemical Biology, National Institute of Chemical Physics and Biophysics, Akadeemia tee 23, 12618 Tallinn, EstoniaThis study aimed to characterize the ATP-synthesis by oxidative phosphorylation in colorectal cancer (CRC) and premalignant colon polyps in relation to molecular biomarkers KRAS and BRAF. This prospective study included 48 patients. Resected colorectal polyps and postoperative CRC tissue with adjacent normal tissue (control) were collected. Patients with polyps and CRC were divided into three molecular groups: <i>KRAS</i> mutated, <i>BRAF</i> mutated and <i>KRAS/BRAF</i> wild-type. Mitochondrial respiration in permeabilized tissue samples was observed using high resolution respirometry. ADP-activated respiration rate (V<sub>max</sub>) and an apparent affinity of mitochondria to ADP, which is related to mitochondrial outer membrane (MOM) permeability, were determined. Clear differences were present between molecular groups. <i>KRAS</i> mutated CRC group had lower V<sub>max</sub> values compared to wild-type; however, the V<sub>max</sub> value was higher than in the control group, while MOM permeability did not change. This suggests that <i>KRAS</i> mutation status might be involved in acquiring oxidative phenotype. <i>KRAS</i> mutated polyps had higher V<sub>max</sub> values and elevated MOM permeability as compared to the control. <i>BRAF</i> mutated CRC and polyps had reduced respiration and altered MOM permeability, indicating a glycolytic phenotype. To conclude, prognostic biomarkers KRAS and BRAF are likely related to the metabolic phenotype in CRC and polyps. Assessment of the tumor mitochondrial ATP synthesis could be a potential component of patient risk stratification.https://www.mdpi.com/2072-6694/12/4/815energy metabolismcolorectal cancercolorectal polypsmitochondriaoxidative phosphorylation<i>KRAS</i> |
| spellingShingle | Egle Rebane-Klemm Laura Truu Leenu Reinsalu Marju Puurand Igor Shevchuk Vladimir Chekulayev Natalja Timohhina Kersti Tepp Jelena Bogovskaja Vladimir Afanasjev Külliki Suurmaa Vahur Valvere Tuuli Kaambre Mitochondrial Respiration in <i>KRAS</i> and <i>BRAF</i> Mutated Colorectal Tumors and Polyps Cancers energy metabolism colorectal cancer colorectal polyps mitochondria oxidative phosphorylation <i>KRAS</i> |
| title | Mitochondrial Respiration in <i>KRAS</i> and <i>BRAF</i> Mutated Colorectal Tumors and Polyps |
| title_full | Mitochondrial Respiration in <i>KRAS</i> and <i>BRAF</i> Mutated Colorectal Tumors and Polyps |
| title_fullStr | Mitochondrial Respiration in <i>KRAS</i> and <i>BRAF</i> Mutated Colorectal Tumors and Polyps |
| title_full_unstemmed | Mitochondrial Respiration in <i>KRAS</i> and <i>BRAF</i> Mutated Colorectal Tumors and Polyps |
| title_short | Mitochondrial Respiration in <i>KRAS</i> and <i>BRAF</i> Mutated Colorectal Tumors and Polyps |
| title_sort | mitochondrial respiration in i kras i and i braf i mutated colorectal tumors and polyps |
| topic | energy metabolism colorectal cancer colorectal polyps mitochondria oxidative phosphorylation <i>KRAS</i> |
| url | https://www.mdpi.com/2072-6694/12/4/815 |
| work_keys_str_mv | AT eglerebaneklemm mitochondrialrespirationinikrasiandibrafimutatedcolorectaltumorsandpolyps AT lauratruu mitochondrialrespirationinikrasiandibrafimutatedcolorectaltumorsandpolyps AT leenureinsalu mitochondrialrespirationinikrasiandibrafimutatedcolorectaltumorsandpolyps AT marjupuurand mitochondrialrespirationinikrasiandibrafimutatedcolorectaltumorsandpolyps AT igorshevchuk mitochondrialrespirationinikrasiandibrafimutatedcolorectaltumorsandpolyps AT vladimirchekulayev mitochondrialrespirationinikrasiandibrafimutatedcolorectaltumorsandpolyps AT nataljatimohhina mitochondrialrespirationinikrasiandibrafimutatedcolorectaltumorsandpolyps AT kerstitepp mitochondrialrespirationinikrasiandibrafimutatedcolorectaltumorsandpolyps AT jelenabogovskaja mitochondrialrespirationinikrasiandibrafimutatedcolorectaltumorsandpolyps AT vladimirafanasjev mitochondrialrespirationinikrasiandibrafimutatedcolorectaltumorsandpolyps AT kullikisuurmaa mitochondrialrespirationinikrasiandibrafimutatedcolorectaltumorsandpolyps AT vahurvalvere mitochondrialrespirationinikrasiandibrafimutatedcolorectaltumorsandpolyps AT tuulikaambre mitochondrialrespirationinikrasiandibrafimutatedcolorectaltumorsandpolyps |