Open Access

CHCHD2 mediates glioblastoma cell proliferation, mitochondrial metabolism, hypoxia‑induced invasion and therapeutic resistance

  • Authors:
    • Jan C. Lumibao
    • Payton L. Haak
    • Vladimir L. Kolossov
    • Jee-Wei Emily Chen
    • Jeremy Stutchman
    • Alejandra Ruiz
    • Mayandi Sivaguru
    • Jann N. Sarkaria
    • Brendan A.C. Harley
    • Andrew J. Steelman
    • H. Rex Gaskins
  • View Affiliations

  • Published online on: August 25, 2023     https://doi.org/10.3892/ijo.2023.5565
  • Article Number: 117
  • Copyright: © Lumibao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Glioblastoma (GBM) is the most common and malignant primary brain tumor affecting adults and remains incurable. The mitochondrial coiled‑coil‑helix‑coiled‑coil‑helix domain‑containing protein 2 (CHCHD2) has been demonstrated to mediate mitochondrial respiration, nuclear gene expression and cell migration; however, evidence of this in GBM is lacking. In the present study, it was hypothesized that CHCHD2 may play a functional role in U87 GBM cells expressing the constitutively active epidermal growth factor receptor variant III (EGFRvIII). The amplification of the CHCHD2 gene was found to be associated with a decreased patient overall and progression‑free survival. The CHCHD2 mRNA levels were increased in high‑vs. low‑grade glioma, IDH‑wt GBMs, and in tumor vs. non‑tumor tissue. Additionally, CHCHD2 protein expression was greatest in invasive, EGFRvIII‑expressing patient‑derived samples. The CRISPR‑Cas9‑mediated knockout of CHCHD2 in EGFRvIII‑expressing U87 cells resulted in an altered mitochondrial respiration and glutathione status, in decreased cell growth and invasion under both normoxic and hypoxic conditions, and in an enhanced sensitivity to cytotoxic agents. CHCHD2 was distributed in both the mitochondria and nuclei of U87 and U87vIII cells, and the U87vIII cells exhibited a greater nuclear expression of CHCHD2 compared to isogenic U87 cells. Incubation under hypoxic conditions, serum starvation and the reductive unfolding of CHCHD2 induced the nuclear accumulation of CHCHD2 in both cell lines. Collectively, the findings of the present study indicate that CHCHD2 mediates a variety of GBM characteristics, and highlights mitonuclear retrograde signaling as a pathway of interest in GBM cell biology.
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November-2023
Volume 63 Issue 5

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Lumibao JC, Haak PL, Kolossov VL, Chen JE, Stutchman J, Ruiz A, Sivaguru M, Sarkaria JN, Harley BA, Steelman AJ, Steelman AJ, et al: CHCHD2 mediates glioblastoma cell proliferation, mitochondrial metabolism, hypoxia‑induced invasion and therapeutic resistance. Int J Oncol 63: 117, 2023.
APA
Lumibao, J.C., Haak, P.L., Kolossov, V.L., Chen, J.E., Stutchman, J., Ruiz, A. ... Gaskins, H. (2023). CHCHD2 mediates glioblastoma cell proliferation, mitochondrial metabolism, hypoxia‑induced invasion and therapeutic resistance. International Journal of Oncology, 63, 117. https://doi.org/10.3892/ijo.2023.5565
MLA
Lumibao, J. C., Haak, P. L., Kolossov, V. L., Chen, J. E., Stutchman, J., Ruiz, A., Sivaguru, M., Sarkaria, J. N., Harley, B. A., Steelman, A. J., Gaskins, H."CHCHD2 mediates glioblastoma cell proliferation, mitochondrial metabolism, hypoxia‑induced invasion and therapeutic resistance". International Journal of Oncology 63.5 (2023): 117.
Chicago
Lumibao, J. C., Haak, P. L., Kolossov, V. L., Chen, J. E., Stutchman, J., Ruiz, A., Sivaguru, M., Sarkaria, J. N., Harley, B. A., Steelman, A. J., Gaskins, H."CHCHD2 mediates glioblastoma cell proliferation, mitochondrial metabolism, hypoxia‑induced invasion and therapeutic resistance". International Journal of Oncology 63, no. 5 (2023): 117. https://doi.org/10.3892/ijo.2023.5565