Skip to main content

Advertisement

SpringerLink
Log in

Hypoxia-induced ROS promotes mitochondrial fission and cisplatin chemosensitivity via HIF-1α/Mff regulation in head and neck squamous cell carcinoma

  • Original Article
  • Published:
Cellular Oncology Aims and scope Submit manuscript

Abstract

Purpose

Chemotherapy based on cisplatin (CDDP) has been established as the treatment of choice for head and neck squamous cell carcinoma (HNSCC). Malignant tumors respond to microenvironmental alterations through a dynamic balance between mitochondrial fission and fusion. HNSCCs are known to exhibit hypoxic conditions, yet the respective effects and underlying mechanisms of hypoxia on chemosensitivity and mitochondrial dynamics remain to be resolved.

Methods

The effect of hypoxia on the chemosensitivity of HNCC cells was determined by flow cytometry. Mitochondrial fission factor (Mff) expression was assessed by RT-PCR and Western blotting in hypoxic HNSCC cells, and further verified in primary CDDP-sensitive and CDDP-resistant HSNCC samples. The biological function of Mff was evaluated by loss of function and gain of function analyses, both in vitro and in vivo.

Results

We found that hypoxia promoted mitochondrial fission and CDDP sensitivity in HNSCC cells. Importantly, Mff was found to be correlated with chemosensitivity in primary clinical samples under hypoxic conditions. Hypoxia-inducible factor 1α (HIF-1α) was found to markedly increase Mff transcription and to directly bind to Mff. Hypoxia enhanced the release of reactive oxygen species (ROS) and upregulated the expression of Mff via HIF-1α in HNSCC cells. ROS depletion in HNSCC cells attenuated HIF-1α expression, Mff expression and mitochondrial fission. Moreover, Mff knockdown led to suppression of hypoxia-induced mitochondrial fission and to decreased CDDP chemosensitivity in vivo and in vitro.

Conclusions

Our findings indicate that hypoxia-induced release of ROS can promote mitochondrial fission and CDDP chemosensitivity via HIF1α/Mff regulation in HNSCC cells, indicating that Mff may serve as a biomarker to predict neoadjuvant chemosensitivity in HNSCC patients and as a target for overcoming chemoresistance.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Data Availability

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Abbreviations

CDDP:

Cisplatin

HNSCC:

Head and neck squamous cell carcinoma

ROS:

Reactive oxygen species

SLC2A1:

Solute carrier family 2 member 1

PDGFB:

Platelet-derived growth factor B

VEGFA:

Vascular endothelial growth factor A

References

  1. F. Kamangar, G.M. Dores, W.F. Anderson, Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J. Clin. Oncol. 24, 2137–2150 (2006)

    Article  Google Scholar 

  2. K. Wu, J.S. Lei, Y.Y. Mao, W. Cao, H.J. Wu, Z.H. Ren, Prediction of flap compromise by preoperative coagulation parameters in head and neck cancer patients. J. Oral. Maxillofac. Surg. 76, 2453 e2451-2453 e2457 (2018)

    Google Scholar 

  3. C.R. Leemans, B.J. Braakhuis, R.H. Brakenhoff, The molecular biology of head and neck cancer. Nat. Rev. Cancer 11, 9–22 (2011)

  4. J.K. Jacinto, J. Co, M.B. Mejia, E.E. Regala, The evidence on effectiveness of weekly vs triweekly cisplatin concurrent with radiotherapy in locally advanced head and neck squamous cell carcinoma (HNSCC): a systematic review and meta-analysis. Br. J. Radiol. 90, 20170442 (2017)

    Article  Google Scholar 

  5. A. Brumwell, L. Fell, L. Obress, J. Uniacke, Hypoxia influences polysome distribution of human ribosomal protein S12 and alternative splicing of ribosomal protein mRNAs. RNA (2020). https://doi.org/10.1261/rna.070318.119

    Article  PubMed  PubMed Central  Google Scholar 

  6. L. Gao, Z.C. Dou, W.H. Ren, S.M. Li, X. Liang, K.Q. Zhi, CircCDR1as upregulates autophagy under hypoxia to promote tumor cell survival via AKT/ERK(1/2)/mTOR signaling pathways in oral squamous cell carcinomas. Cell Death Dis. 10, 745 (2019)

    Article  Google Scholar 

  7. A. Carreau, B. El Hafny-Rahbi, A. Matejuk, C. Grillon, C. Kieda, Why is the partial oxygen pressure of human tissues a crucial parameter? small molecules and hypoxia. J. Cell Mol. Med. 15, 1239–1253 (2011)

    Article  CAS  Google Scholar 

  8. Y. Han, B. Kim, U. Cho, I.S. Park, S.I. Kim, D.N. Dhanasekaran, B.K. Tsang, Y.S. Song, Mitochondrial fission causes cisplatin resistance under hypoxic conditions via ROS in ovarian cancer cells. Oncogene 38, 7089–7105 (2019)

    Article  CAS  Google Scholar 

  9. E. Wiechec, K.T. Hansson, L. Alexandersson, J.I. Jonsson, K. Roberg, Hypoxia mediates differential response to Anti-EGFR therapy in HNSCC cells. Int. J. Mol. Sci. 18, 943 (2017)

  10. S. Prasad, S.C. Gupta, A.K. Tyagi, Reactive oxygen species (ROS) and cancer: role of antioxidative nutraceuticals. Cancer Lett. 387, 95–105 (2017)

    Article  CAS  Google Scholar 

  11. L. Tretter, A. Patocs, C. Chinopoulos, Succinate, an intermediate in metabolism, signal transduction, ROS, hypoxia, and tumorigenesis. Biochem. Biophys. Acta 1857, 1086–1101 (2016)

  12. J. Kim, I.B. Barsoum, H. Loh, J.F. Pare, D.R. Siemens, C.H. Graham, Inhibition of hypoxia-inducible factor 1 alpha accumulation by glyceryl trinitrate and cyclic guanosine monophosphate. Biosci. Rep. 40, BSR20192345 (2020)

  13. J. Zhang, Q. Zhang, Y. Lou, Q. Fu, Q. Chen, T. Wei, J. Yang, J. Tang, J. Wang, Y. Chen, X. Zhang, J. Zhang, X. Bai, T. Liang, Hypoxia-inducible factor-1alpha/interleukin-1beta signaling enhances hepatoma epithelial-mesenchymal transition through macrophages in a hypoxic-inflammatory microenvironment. Hepatology 67, 1872–1889 (2018)

    Article  CAS  Google Scholar 

  14. C.P. Cui, C.C. Wong, A.K. Kai, D.W. Ho, E.Y. Lau, Y.M. Tsui, L.K. Chan, T.T. Cheung, K.S. Chok, A.C.Y. Chan, R.C. Lo, J.M. Lee, T.K. Lee, I.O.L. Ng, SENP1 promotes hypoxia-induced cancer stemness by HIF-1alpha deSUMOylation and SENP1/HIF-1alpha positive feedback loop. Gut 66, 2149–2159 (2017)

    Article  CAS  Google Scholar 

  15. D.F. Suen, K.L. Norris, R.J. Youle, Mitochondrial dynamics and apoptosis. Genes Dev. 22, 1577–1590 (2008)

    Article  CAS  Google Scholar 

  16. H. Chen, D.C.J.C.M. Chan, Mitochondrial dynamics in regulating the unique phenotypes of cancer and stem cells. Cell Metab. 26, 39–48 (2017)

    Article  CAS  Google Scholar 

  17. Y. Han, U. Cho, S. Kim, I.S. Park, J.H. Cho, D.N. Dhanasekaran, S.S. Yong, Tumor microenvironment on mitochondrial dynamics and chemoresistance in cancer. Free Radical Res. 52, 1271–1287 (2018)

    Article  CAS  Google Scholar 

  18. T. Tian, X. Lv, G. Pan, Y. Lu, W. Chen, W. He, X. Lei, H. Zhang, M. Liu, S. Sun, Z. Ou, X. Lin, L. Cai, L. He, Z. Tu, X. Wang, B.A. Tannous, S. Ferrone, J. Li, S. Fan, Long noncoding RNA MPRL promotes mitochondrial fission and cisplatin chemosensitivity via disruption of pre-miRNA processing. Clin Cancer Res. 25, 3673–3688 (2019)

    Article  CAS  Google Scholar 

  19. S. Fan, T. Tian, W. Chen, X. Lv, X. Lei, H. Zhang, S. Sun, L. Cai, G. Pan, L. He, Z. Ou, X. Lin, X. Wang, M.F. Perez, Z. Tu, S. Ferrone, B.A. Tannous, J. Li, Mitochondrial miRNA determines chemoresistance by reprogramming metabolism and regulating mitochondrial transcription. Cancer Res. 79, 1069–1084 (2019)

    Article  CAS  Google Scholar 

  20. P.H. Yan, L. Wang, H. Chen, F.Q. Yu, L. Guo, Y. Liu, W.J. Zhang, Y.L. Bai, LncRNA RUNX1-IT1 inhibits proliferation and promotes apoptosis of hepatocellular carcinoma by regulating MAPK pathways. Eur. Rev. Med. Pharmacol. Sci. 23, 8287–8294 (2019)

  21. Q. Chen, K. Wu, X. Qin, Y. Yu, X. Wang, K. Wei, LASP1 promotes proliferation, metastasis, invasion in head and neck squamous cell carcinoma and through direct interaction with HSPA1A. J. Cell Mol. Med. 24, 1626–1639 (2019)

    Article  Google Scholar 

  22. D.F. Kashatus, K.H. Lim, D.C. Brady, N.L. Pershing, A.D. Cox, C.M. Counter, RALA and RALBP1 regulate mitochondrial fission at mitosis. Nat. Cell Biol. 13, 1108–1115 (2011)

    Article  CAS  Google Scholar 

  23. P. Amini, D. Stojkov, A. Felser, C.B. Jackson, C. Courage, A. Schaller, L. Gelman, M.E. Soriano, J.M. Nuoffer, L. Scorrano, C. Benarafa, S. Yousefi, H.U. Simon, Neutrophil extracellular trap formation requires OPA1-dependent glycolytic ATP production. Nat. Commun. 9, 2958 (2018)

    Article  Google Scholar 

  24. O. Kujan, K. Shearston, C.S. Farah, The role of hypoxia in oral cancer and potentially malignant disorders: a review. J. Oral Pathol. Med. 46, 246–252 (2017)

  25. Y. Niu, L. Bao, Y. Chen, C. Wang, M. Luo, B. Zhang, M. Zhou, J.E. Wang, Y.V. Fang, A. Kumar, C. Xing, Y. Wang, W. Luo, HIF-2-induced long non-coding RNA RAB11B-AS1 promotes hypoxia-mediated angiogenesis and breast cancer metastasis. Cancer Res. 80, 964–975 (2020)

    Article  CAS  Google Scholar 

  26. H. Lee, Y. Yoon, Mitochondrial fission and fusion. Biochem. Soc. Trans. 44, 1725–1735 (2016)

    Article  CAS  Google Scholar 

  27. M.J. Molnar, G.G. Kovacs, Mitochondrial diseases. Handb. Clin. Neurol. 145, 147–155 (2017)

  28. A. Bose, M.F. Beal, Mitochondrial dysfunction in Parkinson’s disease. J. Neurochem. 139(Suppl 1), 216–231 (2016)

    Article  CAS  Google Scholar 

  29. B. Li, W. Wang, Z. Li, Z. Chen, X. Zhi, J. Xu, Q. Li, L. Wang, X. Huang, L.J.C.L. Wang, MicroRNA-148a-3p enhances cisplatin cytotoxicity in gastric cancer through mitochondrial fission induction and cyto-protective autophagy suppression. Cancer Lett. 410, 212–227 (2017)

    Article  CAS  Google Scholar 

  30. B. Kong, H. Tsuyoshi, M. Orisaka, D.B. Shieh, Y. Yoshida, B.K. Tsang, Mitochondrial dynamics regulating chemoresistance in gynecological cancers. Ann. N. Y. Acad. Sci. 1350, 1–16 (2015)

    Article  CAS  Google Scholar 

  31. J.H. Seo, Y.C. Chae, A.V. Kossenkov, Y.G. Lee, H.Y. Tang, E. Agarwal, D.I. Gabrilovich, L.R. Languino, D.W. Speicher, P.K. Shastrula, A.M. Storaci, S. Ferrero, G. Gaudioso, M. Caroli, D. Tosi, M. Giroda, V. Vaira, V.W. Rebecca, M. Herlyn, M. Xiao, D. Fingerman, A. Martorella, E. Skordalakes, D.C. Altieri, MFF regulation of mitochondrial cell death is a therapeutic target in cancer. Cancer Res. 79, 6215–6226 (2019)

    Article  CAS  Google Scholar 

  32. J.H. Seo, E. Agarwal, Y.C. Chae, Y.G. Lee, D.S. Garlick, A.M. Storaci, S. Ferrero, G. Gaudioso, U. Gianelli, V. Vaira, D.C. Altieri, Mitochondrial fission factor is a novel Myc-dependent regulator of mitochondrial permeability in cancer. EBioMedicine 48, 353–363 (2019)

    Article  Google Scholar 

  33. Y. Xie, Y. Lv, Y. Zhang, Z. Liang, L. Han, Y. Xie, LATS2 promotes apoptosis in non-small cell lung cancer A549 cells via triggering Mff-dependent mitochondrial fission and activating the JNK signaling pathway. Biomed. Pharmacother. Biomed. Pharmacother. 109, 679–689 (2019)

    Article  CAS  Google Scholar 

  34. S. Jieensinue, H. Zhu, G. Li, K. Dong, M. Liang, Y. Li, Tanshinone IIA reduces SW837 colorectal cancer cell viability via the promotion of mitochondrial fission by activating JNK-Mff signaling pathways. BMC Cell Biol. 19, 21 (2018)

    Article  Google Scholar 

  35. Y. He, X. Fang, J. Shi, X. Li, M. Xie, X. Liu, Apigenin attenuates pulmonary hypertension by inducing mitochondria-dependent apoptosis of PASMCs via inhibiting the hypoxia inducible factor 1alpha-KV1.5 channel pathway. Chem. Biol. Interact. 317, 108942 (2020)

    Article  CAS  Google Scholar 

  36. H.S. Li, Y.N. Zhou, L. Li, S.F. Li, D. Long, X.L. Chen, J.B. Zhang, L. Feng, Y.P. Li, HIF-1alpha protects against oxidative stress by directly targeting mitochondria. Redox Biol. 25, 101109 (2019)

    Article  CAS  Google Scholar 

  37. I. Mylonis, M. Kourti, M. Samiotaki, G. Panayotou, G. Simos, Mortalin-mediated and ERK-controlled targeting of HIF-1alpha to mitochondria confers resistance to apoptosis under hypoxia. J. Cell Sci. 130, 466–479 (2017)

    CAS  PubMed  Google Scholar 

  38. X. Chen, J.M. Yao, X. Fang, C. Zhang, Y.S. Yang, C.P. Hu, Q. Chen, G.W. Zhong, Hypoxia promotes pulmonary vascular remodeling via HIF-1alpha to regulate mitochondrial dynamics. J. Geriatric Cardiol. 16, 855–871 (2019)

  39. D.C. Fuhrmann, B. Brune, Mitochondrial composition and function under the control of hypoxia. Redox Biol. 12, 208–215 (2017)

    Article  CAS  Google Scholar 

  40. J. Cheng, H.L. Yang, C.J. Gu, Y.K. Liu, J. Shao, R. Zhu, Y.Y. He, X.Y. Zhu, M.Q. Li, Melatonin restricts the viability and angiogenesis of vascular endothelial cells by suppressing HIF-1alpha/ROS/VEGF. Int. J. Mol. Med. 43, 945–955 (2019)

    CAS  PubMed  Google Scholar 

  41. M. Shida, Y. Kitajima, J. Nakamura, K. Yanagihara, K. Baba, K. Wakiyama, H. Noshiro, Impaired mitophagy activates mtROS/HIF-1alpha interplay and increases cancer aggressiveness in gastric cancer cells under hypoxia. Int. J. Oncol. 48, 1379–1390 (2016)

    Article  CAS  Google Scholar 

Download references

Funding

This work was supported by the grants from the National Natural Science Foundation for Youth Program of China (81902808, Yan Li).

Author information

Authors and Affiliations

  1. Department of Stomatology, Second Xiangya Hospital, Central South University, Renmin road, No. 139, Changsha, 410011, Hunan, China

    Kun Wu, Sheng Zhang & Han-jiang Wu

  2. Department of Anesthesiology, Second Xiangya Hospital, Central South University, Changsha, Hunan, China

    Yuan-yuan Mao

  3. Department of Stomatology Qingpu Branch of Zhongshan Hospital, Fudan University, Shanghai, China

    Qi Chen

  4. Department of Stomatology, Xinhua Hospital Affiliated To Shanghai Jiao Tong University, Shanghai, China

    Bolin Zhang

  5. Precision Research Center for Refractory Diseases, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No. 650 Xin Songjia Road, Shanghai, 200025, China

    Yan Li

  6. Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China

    Yan Li

Authors
  1. Kun Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yuan-yuan Mao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Qi Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bolin Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sheng Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Han-jiang Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

WK and LY analyzed and interpreted the data. WK was a major contributor in writing the manuscript. ZS, WHJ and LY edited the manuscript. CQ, MYY and ZBL collected the specimens. All authors read and approved the final version of the manuscript.

Corresponding authors

Correspondence to Sheng Zhang, Han-jiang Wu or Yan Li.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Ethical approval

This study was approved by the Ethics Committee of the Second Xiangya Hospital (Approval No. 2020530, 2020/9/14). All animal studies were approved by the Second Xiangya Hospital Animal Ethical and Welfare Committee (Approval No. 2020489, 2020/9/9).

Consent for publication

Written informed consent was obtained from all participants prior to enrollment.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wu, K., Mao, Yy., Chen, Q. et al. Hypoxia-induced ROS promotes mitochondrial fission and cisplatin chemosensitivity via HIF-1α/Mff regulation in head and neck squamous cell carcinoma. Cell Oncol. 44, 1167–1181 (2021). https://doi.org/10.1007/s13402-021-00629-6

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13402-021-00629-6

Keywords

Search

Navigation