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Research Article
Daiqing Wei
The Affiliated Hospital of Southwest Medical University
Corresponding Author
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background：Despite the widespread adoption of chemotherapy, drug resistance has been the major obstacle in tumor elimination of cancer patients. Our aim was to explore the role of TGF-β in osteosarcoma chemo-resistance.
Methods：We performed cytotoxicity analysis of methotrexate (MTX) and cisplatin (CIS) in TGF-β treated osteosarcoma cells. Then a metabolite profile of the core energetic routes was analyzed by 1H-NMR in Saos-2 and MG-63 cell extracts. We detected the expression of succinate dehydrogenase (SDH), STAT1, and Hypoxia-inducible factor 1α (HIF1α) in TGF-β treated osteosarcoma cells, and further tested the effects of these molecules on the cytotoxicity of chemotherapeutic agents. In vivo, we examined the tumor growth and survival time of Saos-2 bearing mice given the combination therapy of chemotherapeutic agents and a HIF1α inhibitor.
Results：Metabolic analysis revealed an enhanced succinate production of osteosarcoma cells after TGF-β treatment. We further found the decrease in SDH expression and the increase in HIF1α expression of TGF-β treated osteosarcoma cells. Consistently, blockade of SDH aggravated the resistance of Saos-2/MG-63 cells to MTX and CIS. Also, a HIF1α inhibitor significantly strengthened the anti-cancer efficacy of chemotherapeutic drugs in mice with osteosarcoma cancer.
Conclusion：Our study demonstrated that TGF-β attenuated the expression of SDH through reducing the transcription factor STAT1. The reduction of SDH then caused the up-regulation of HIF1α, thereby rerouting the glucose metabolism and aggravating chemo-resistance in osteosarcoma cells. Linking tumor cell metabolism to the formation of chemotherapy resistance, our study may guide the development of more effective treatments of osteosarcoma.
Keywords
TGF-β, chemo-resistance, succinate dehydrogenase, osteosarcoma, Hypoxia-inducible factor 1α (HIF1α)
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No competing interests reported.
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CURRENT STATUS: Under Review
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Editorial decision: Major revision
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Received 12 May, 2021
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On 08 May, 2021
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On 07 May, 2021
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On 06 May, 2021
Editor invited
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A new preprint design is coming!
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This preprint is under consideration at BMC Cancer. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research Article
Daiqing Wei
The Affiliated Hospital of Southwest Medical University
Corresponding Author
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Review
Version 1
Posted 10 May, 2021
No community comments so far
Editorial decision: Major revision
On 24 May, 2021
Reviews received
Received 12 May, 2021
Reviewers agreed
On 08 May, 2021
Reviewers agreed
On 07 May, 2021
Reviewers invited
Invitations sent on 07 May, 2021
Editor assigned
On 06 May, 2021
Editor invited
On 06 May, 2021
Submission checks complete
On 06 May, 2021
First submitted
On 26 Apr, 2021
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Cancer Biology
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background：Despite the widespread adoption of chemotherapy, drug resistance has been the major obstacle in tumor elimination of cancer patients. Our aim was to explore the role of TGF-β in osteosarcoma chemo-resistance.
Methods：We performed cytotoxicity analysis of methotrexate (MTX) and cisplatin (CIS) in TGF-β treated osteosarcoma cells. Then a metabolite profile of the core energetic routes was analyzed by 1H-NMR in Saos-2 and MG-63 cell extracts. We detected the expression of succinate dehydrogenase (SDH), STAT1, and Hypoxia-inducible factor 1α (HIF1α) in TGF-β treated osteosarcoma cells, and further tested the effects of these molecules on the cytotoxicity of chemotherapeutic agents. In vivo, we examined the tumor growth and survival time of Saos-2 bearing mice given the combination therapy of chemotherapeutic agents and a HIF1α inhibitor.
Results：Metabolic analysis revealed an enhanced succinate production of osteosarcoma cells after TGF-β treatment. We further found the decrease in SDH expression and the increase in HIF1α expression of TGF-β treated osteosarcoma cells. Consistently, blockade of SDH aggravated the resistance of Saos-2/MG-63 cells to MTX and CIS. Also, a HIF1α inhibitor significantly strengthened the anti-cancer efficacy of chemotherapeutic drugs in mice with osteosarcoma cancer.
Conclusion：Our study demonstrated that TGF-β attenuated the expression of SDH through reducing the transcription factor STAT1. The reduction of SDH then caused the up-regulation of HIF1α, thereby rerouting the glucose metabolism and aggravating chemo-resistance in osteosarcoma cells. Linking tumor cell metabolism to the formation of chemotherapy resistance, our study may guide the development of more effective treatments of osteosarcoma.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
No competing interests reported.
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