Reference SummaryLee SH, Cancers (Basel) 2020 May 28;12(6):
Title |
The Combination of Loss of ALDH1L1 Function and Phenformin Treatment Decreases Tumor Growth in KRAS-Driven Lung Cancer. |
Authors |
Lee SH; Jeon Y; Kang JH; Jang H; Lee H; Kim SY |
Journal |
Cancers (Basel) |
Volume |
12 |
Issue |
6 |
Year |
2020 |
Pages |
|
Abstract |
Lung adenocarcinoma cells express high levels of ALDH1L1, an enzyme of the one-carbon pathway that catalyzes the conversion of 10-formyltetrahydrofolate into tetrahydrofolate and NAD(P)H. In this study, we evaluated the potential of ALDH1L1 as a therapeutic target by deleting the Aldh1l1 gene in Kras(LA2) mice, a model of spontaneous non-small cell lung cancer (NSCLC). Reporter assays revealed KRAS-mediated upregulation of the ALDH1L1 promoter in human NSCLC cells. Aldh1l1(-/-) mice exhibited a normal phenotype, with a 10% decrease in Kras-driven lung tumorigenesis. By contrast, the inhibition of oxidative phosphorylation inhibition using phenformin in Aldh1l1(-/-); Kras(LA2) mice dramatically decreased the number of tumor nodules and tumor area by up to 50%. Furthermore, combined treatment with pan-ALDH inhibitor and phenformin showed a decreased number and area of lung tumors by 70% in the Kras(LA2) lung cancer model. Consistent with this, previous work showed that the combination of ALDH1L1 knockdown and phenformin treatment decreased ATP production by as much as 70% in NSCLS cell lines. Taken together, these results suggest that the combined inhibition of ALDH activity and oxidative phosphorylation represents a promising therapeutic strategy for NSCLC. |
Links |
J:294979 – MGI References 32481524 – National Library of Medicine/PubMed |
| Strain | Model Name | Treatment Agent(s) | Organ Affected | Frequency | Model Details |
|---|---|---|---|---|---|
| C57BL/6-Krastm3Tyj/+ | Lung adenocarcinoma | Lung |
0 |
||
| C57BL/6-Krastm3Tyj/+ | Lung adenocarcinoma |
|
Lung |
0 |
|
| C57BL/6-Krastm3Tyj/+ | Lung adenoma | Lung |
observed |
||
| C57BL/6-Krastm3Tyj/+ | Lung adenoma | Lung |
observed |
||
| C57BL/6-Krastm3Tyj/+ | Lung adenoma |
|
Lung |
observed |
|
| C57BL/6-Aldh1l1tm1b(KOMP)Wtsi Krastm3Tyj/+ | Lung adenoma | Lung |
observed |
||
| C57BL/6-Aldh1l1tm1b(KOMP)Wtsi Krastm3Tyj/+ | Lung adenoma |
|
Lung |
observed |
|
| C57BL/6-Krastm3Tyj/+ | Lung adenoma |
|
Lung |
observed |
|
| C57BL/6-Krastm3Tyj/+ | Lung hyperplasia | Lung |
observed |
||
| C57BL/6-Krastm3Tyj/+ | Lung hyperplasia | Lung |
observed |
||
| C57BL/6-Krastm3Tyj/+ | Lung hyperplasia |
|
Lung |
observed |
|
| C57BL/6-Aldh1l1tm1b(KOMP)Wtsi Krastm3Tyj/+ | Lung hyperplasia | Lung |
observed |
||
| C57BL/6-Aldh1l1tm1b(KOMP)Wtsi Krastm3Tyj/+ | Lung hyperplasia |
|
Lung |
observed |
|
| C57BL/6-Krastm3Tyj/+ | Lung hyperplasia |
|
Lung |
observed |
|
| C57BL/6-Krastm3Tyj/+ | Lung tumor | Lung |
observed - 100 |
||
| C57BL/6-Krastm3Tyj/+ | Lung tumor | Lung |
observed - 100 |
||
| C57BL/6-Krastm3Tyj/+ | Lung tumor |
|
Lung |
observed - 100 |
|
| C57BL/6-Aldh1l1tm1b(KOMP)Wtsi Krastm3Tyj/+ | Lung tumor | Lung |
observed - 100 |
||
| C57BL/6-Aldh1l1tm1b(KOMP)Wtsi Krastm3Tyj/+ | Lung tumor |
|
Lung |
observed - 100 |