Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis
- The Feinberg School of Medicine, Northwestern University, United States
- University of Tampere, Finland
Figures
Figure 1 with 1 supplement
Metformin inhibits mitochondrial complex I function.
(A) Relative mitochondrial oxygen consumption rate (OCR) of intact Control-HCT 116 p53−/− and (B) NDI1-HCT 116 p53−/− cells treated with metformin in complete media for 24 hr. (C) Relative complex I …
Figure 1—figure supplement 1
NDI1 expression slightly increases oxygen consumption.
(A) Basal mitochondrial oxygen consumption rate of Control-HCT 116 p53−/− (+BFP) and NDI1-HCT 116 p53−/− cells normalized to Control-HCT 116 p53−/− cells. (B) Coupled mitochondrial oxygen …
Figure 2 with 2 supplements
Metformin decreases cell proliferation by inhibiting mitochondrial complex I.
(A) Percentage of live Control-HCT 116 p53−/− or (B) NDI1-HCT 116 p53−/− treated with metformin for 72 hr in media containing 10 mM glucose. (C) Percentage of live Control-HCT116 p53−/− or (D) …
Figure 2—figure supplement 1
Metformin decreases cellular proliferation through inhibition of mitochondrial complex I function in HCT 116 p53+/+ cells.
(A) Relative mitochondrial oxygen consumption rate of Control-HCT 116 p53+/+ cells and (B) NDI1-HCT 116 p53+/+ cells treated with metformin in complete media for 24 hr. (C) Cell number of …
Figure 2—figure supplement 2
Metformin decreases cellular proliferation through inhibition of mitochondrial complex I function in A549 cells.
(A) Relative mitochondrial oxygen consumption rate of Control-A549 cells and (B) NDI1-A549 cells treated with metformin in complete media for 24 hr. (C) Cell number of Control-A549 cells and (D) …
Figure 3 with 2 supplements
Phenformin decreases cell proliferation by inhibiting mitochondrial complex I.
(A) Relative mitochondrial oxygen consumption rate (OCR) of intact Control-HCT 116 p53−/− and (B) NDI1-HCT 116 p53−/− cells treated with phenformin in complete media for 24 hr. (C) Relative complex …
Figure 3—figure supplement 1
Metformin inhibits mitochondrial complex I of CCL16 cells.
(A) Relative mitochondrial oxygen consumption rate of Control-CCL16 cells and (B) NDI1-CCL16 cells treated with metformin in complete media for 20 min. (C) Percentage of live Control-CCL16, (D) …
Figure 3—figure supplement 2
Phenformin inhibits mitochondrial complex I of CCL16 cells.
(A) Relative mitochondrial oxygen consumption rate of Control-CCL16 cells and (B) NDI1-CCL16 cells treated with metformin in complete media for 20 min. (C) Percentage of live Control-CCL16 or (D) …
Figure 4
Metformin inhibition of complex I requires an intact mitochondrial inner membrane potential.
(A) Complex I (2 mM malate, 10 mM pyruvate)-driven oxygen consumption rate of saponin permeabilized Control-HCT 116 p53−/− cells over time. At t = 5 min permeabilized cells were treated with either …
Figure 5
Metformin reversibly inhibits mitochondrial complex I.
(A) Complex I (2 mM malate, 10 mM pyruvate)-driven oxygen consumption rate of saponin permeabilized Control-HCT 116 p53−/− cells over time. At t = 5 min permeabilized cells were exposed to 1 mM …
Figure 6
Metformin reduces HIF-1 activation through inhibition of mitochondrial complex I.
(A and B) H2O2 levels emitted by mitochondria isolated from Control-HCT 116 p53−/− and NDI1-HCT 116 p53−/− cells respiring on 2 mM malate and 10 mM pyruvate. Mitochondria were treated with 1 mM …
Figure 7 with 3 supplements
Metformin inhibits mitochondrial complex I to diminish tumor growth.
(A) Average tumor volume in mice injected with 3 × 106 Control-HCT 116 p53−/− or NDI1-HCT 116 p53−/− cells injected into the left flank of J:Nu mice. Mice were given ad libitum, water free of …
Figure 7—figure supplement 1
Metformin treatment of tumor bearing mice does not alter blood glucose, plasma lactate, IGF-1, and insulin levels.
(A) Blood glucose levels of mice injected with 3 × 106 Control-HCT 116 p53−/− or NDI1HCT 116 p53−/− cells into the left flank of J:Nu mice. Mice were treated with water free of metformin or were …
Figure 7—figure supplement 2
Metformin inhibits cellular proliferation and pro- proliferative signaling via complex I inhibition.
(A) Immunoblot for the complex I protein NDUFS3 in Control-A549 cells expressing control shRNA and NDI-A549 cells expressing a shRNA specific for the NDUFS3 subunit. (B) Relative mitochondrial …
Figure 7—figure supplement 3
NDI1 expressing A549 cells are refractory to metformin treatment in a xenograft model of tumor growth.
(A) Hypoxic induction of HIF1a in Control-A549 and NDI1-A549 cells treated with 0 or 2 mM metformin for 24 hr then placed in normoxia (21% O2), hypoxia (1.5% O2) or treated with Deferoxamine (DFO) …
