EGFR-targeted mAb therapy modulates autophagy in head and neck squamous cell carcinoma through NLRX1-TUFM protein complex

Y. Lei, B. A. Kansy, J. Li, L. Cong, Y. Liu, S. Trivedi, Haitao Wen, J. P.Y. Ting, H. Ouyang, R. L. Ferris

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Epidermal growth factor receptor (EGFR)-targeted therapy in head and neck squamous cell carcinoma (HNSCC) patients frequently results in tumor resistance to treatment. Autophagy is an emerging underlying resistance mechanism, however, the molecular autophagy machinery in HNSCC cells and potential biomarkers of patient response to EGFR-targeted therapy remain insufficiently characterized. Here we show that the EGFR blocking with cetuximab leads to varied autophagic responses, which modulate cancer cell susceptibility to EGFR inhibition. Inhibition of autophagy sensitizes HNSCC cells to EGFR blockade. Importantly, we identify a novel signaling hub centering on the NLRX1 (nucleotide-binding, lots of leucine-rich repeats-containing protein member X1)-TUFM (Tu translation elongation factor mitochondrial) protein complex, promoting autophagic flux. Defects in the expression of either NLRX1 or TUFM result in compromised autophagy when treated with EGFR inhibitors. As a previously undefined autophagy-promoting mechanism, we found that TUFM serves as a novel anchorage site, recruiting Beclin-1 to mitochondria, promoting its polyubiquitination, and interfering with its interaction with Rubicon. This protein complex is also essential for endoplasmic reticulum stress signaling induction, possibly as an additional mechanism to promote autophagy. Utilizing tumor specimens from a novel neoadjuvant clinical trial, we show that increased expression of the autophagy adaptor protein, SQSTM1/p62, is associated with poor response to cetuximab therapy. These findings expand our understanding of the components involved in HNSCC autophagy machinery that responds to EGFR inhibitors, and suggest potential combinatorial approaches to enhance its therapeutic efficacy.

Original languageEnglish (US)
Pages (from-to)4698-4707
Number of pages10
JournalOncogene
Volume35
Issue number36
DOIs
StatePublished - Sep 8 2016

Fingerprint

Autophagy
Epidermal Growth Factor Receptor
Proteins
Therapeutics
Peptide Elongation Factor Tu
Neoplasms
Endoplasmic Reticulum Stress
Carcinoma, squamous cell of head and neck
Mitochondrial Proteins
Mitochondria
Nucleotides
Biomarkers
Clinical Trials

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Lei, Y., Kansy, B. A., Li, J., Cong, L., Liu, Y., Trivedi, S., ... Ferris, R. L. (2016). EGFR-targeted mAb therapy modulates autophagy in head and neck squamous cell carcinoma through NLRX1-TUFM protein complex. Oncogene, 35(36), 4698-4707. https://doi.org/10.1038/onc.2016.11

EGFR-targeted mAb therapy modulates autophagy in head and neck squamous cell carcinoma through NLRX1-TUFM protein complex. / Lei, Y.; Kansy, B. A.; Li, J.; Cong, L.; Liu, Y.; Trivedi, S.; Wen, Haitao; Ting, J. P.Y.; Ouyang, H.; Ferris, R. L.

In: Oncogene, Vol. 35, No. 36, 08.09.2016, p. 4698-4707.

Research output: Contribution to journalArticle

Lei, Y, Kansy, BA, Li, J, Cong, L, Liu, Y, Trivedi, S, Wen, H, Ting, JPY, Ouyang, H & Ferris, RL 2016, 'EGFR-targeted mAb therapy modulates autophagy in head and neck squamous cell carcinoma through NLRX1-TUFM protein complex', Oncogene, vol. 35, no. 36, pp. 4698-4707. https://doi.org/10.1038/onc.2016.11
Lei, Y. ; Kansy, B. A. ; Li, J. ; Cong, L. ; Liu, Y. ; Trivedi, S. ; Wen, Haitao ; Ting, J. P.Y. ; Ouyang, H. ; Ferris, R. L. / EGFR-targeted mAb therapy modulates autophagy in head and neck squamous cell carcinoma through NLRX1-TUFM protein complex. In: Oncogene. 2016 ; Vol. 35, No. 36. pp. 4698-4707.
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