Dataset Information

Disrupting metformin adaptation of hepatocellular carcinoma by targeting TOMM34/ATP5B axis

ABSTRACT: As a well-known anti-diabetic drug, metformin has been repurposed for cancer treatment, but drug resistance and tumor metastasis observed recently have challenged its further application. Here, we found that long-term metformin exposure led to metabolic adaptation of HCC cells, which was characterized by obvious epithelial-mesenchymal transition (EMT) phenotype and compensatory elevated oxidative phosphorylation (OXPHOS). TOMM34, a translocase of the outer mitochondrial membrane, was identified to confer energetic flexibility thus promoting tumor metastasis in response to metformin-induced metabolic stress. Mechanistically, TOMM34 interacted and stabilized ATP5B to preserve F1F0-ATPase activity, which promoted mitochondrial OXPHOS and increased cellular ATP levels. This metabolic preference to OXPHOS suggested a large demand of energy supply of cancer cells to survival and spread under therapeutic stress.

ORGANISM(S): Homo Sapiens

SUBMITTER: Canhua Huang

PROVIDER: PXD035365 | iProX | Thu Jul 14 00:00:00 BST 2022

REPOSITORIES: iProX

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Publications

Disrupting metformin adaptation of liver cancer cells by targeting the TOMM34/ATP5B axis.

Jin Ping P Jiang Jingwen J Zhou Li L Huang Zhao Z Qin Siyuan S Chen Hai-Ning HN Peng Liyuan L Zhang Zhe Z Li Bowen B Luo Maochao M Zhang Tingting T Ming Hui H Ding Ning N Li Lei L Xie Na N Gao Wei W Zhang Wei W Nice Edouard C EC Wei Yuquan Y Huang Canhua C

EMBO molecular medicine 20221102 12

Metformin, a well-known antidiabetic drug, has been repurposed for cancer treatment; however, recently observed drug resistance and tumor metastasis have questioned its further application. Here, we found that long-term metformin exposure led to metabolic adaptation of hepatocellular carcinoma (HCC) cells, which was characterized by an obvious epithelial-mesenchymal transition (EMT) phenotype and compensatory elevation of oxidative phosphorylation (OXPHOS). TOMM34, a translocase of the outer mit ...[more]

PMID: 36321555

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Project description:In a subacute study, male Wistar rats were treated daily by gavage with 800 mg/kg metformin for 1, 3, or 14 consecutive days, followed by necropsy 24h after the last application. The biguanide metformin is a widely used antidiabetic drug, which has received great interest in oncology research in recent years after an epidemiological study showed a link between metformin treatment and a reduced cancer risk in diabetic patients. Since mitochondrial metabolism has become a target for possible cancer therapeutic approaches, especially for tumors relying on oxidative metabolism, mitochondrial complex I inhibition is under discussion to be responsible for the anti-cancer effect of metformin. The known strong complex I inhibitor Rotenone has also shown anti-cancer activity, however is associated with toxic effects. Therefore, we compared metformin and phenformin, another biguanide withdrawn from the marked as antidiabetic due to safety reasons, with rotenone, to elucidate potential mechanisms rendering biguanides apparently less toxic than rotenone. In this context, various blood and tissue parameters as well as histopathology were measured and/or evaluated. Moreover, gene expression profiling was conducted in liver and heart due to the high metabolic activity and high energy demand. All investigations were based on an experimental design previously described for mechanistic investigations of the effects of rotenone. Our examinations regarding gene expression showed that 1630 transcripts were deregulated by rotenone, metformin and/or phenformin in liver, whereas 777 transcripts were deregulated in heart, indicating that the heart is less affected by these compounds. Overall, the mechanistic profile of phenformin appears to be similar to that of rotenone, yet at a quantitatively reduced level, whereas metformin displayed only transient similarities after one day of treatment. These differences are likely due to differential molecular properties of these compounds, especially concerning their effects on mitochondria: Metformin, in contrast to rotenone, requires a certain mitochondrial potential to allow accumulation in this organelle, thereby self-limiting its entry and thus ability to inhibit mitochondrial function, whereas rotenone and to some extent also phenformin can enter mitochondria freely. Thus, our more detailed molecular characterization of these compounds suggests that inhibition of mitochondrial functions can serve as target for an anti-cancer mode of action, yet should be self-limited or balanced to some extent to avoid exhaustion of all energy stores.

Dataset Information

Disrupting metformin adaptation of hepatocellular carcinoma by targeting TOMM34/ATP5B axis

Publications

Disrupting metformin adaptation of liver cancer cells by targeting the TOMM34/ATP5B axis.

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