RANKL triggers resistance to TRAIL-induced cell death in oral squamous cell carcinoma

Purushoth Ethiraj, Yuvaraj Sambandam, Jessica D. Hathaway-Schrader, Azizul Haque, Chad M. Novince, Sakamuri V. Reddy*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


Oral squamous cell carcinoma (OSCC) occurs as a malignancy of the oral cavity. RANK ligand (RANKL) is essential for osteoclast formation/bone resorption. Recently, we showed autoregulation of receptor activator of nuclear factor-κB ligand (RANKL) stimulates OSCC cell proliferation. OSCC cells show resistance to tumor necrosis factor related apoptosis inducing ligand (TRAIL) treatment. Therefore, we hypothesize that RANKL promotes resistance for TRAIL induction of OSCC apoptotic cell death. In this study, SCC14A and SCC74A cells cultured with TRAIL revealed high-level expression of RANKL which increased resistance to TRAIL inhibition of tumor cell proliferation. RANKL stimulation inhibited terminal deoxynucleotidyl transferase dUTP nick end labeling positive staining in TRAIL-treated cells. CRISPR/Cas-9 knockout of RANKL (RANKL-KO) increased caspase-9, caspase-3 activity and cytochrome c release in OSCC cells. RANKL inhibited proapoptotic proteins BAD and BAX expression. TRAIL treatment suppressed the SQSTM1/p62 and RANKL restored the expression. Interestingly, RANKL alone significantly increased proteasome activity. RANKL-KO in OSCC cells inhibited autophagic activity as evidenced by decreased light chain 3B-II and beclin-1 expression. Thus, RANKL stimulation of OSCC tumor cells triggered resistance for TRAIL-induced OSCC cell death. Taken together, blockade of RANKL may inhibit OSCC tumor progression and enhance the potential of TRAIL induced OSCC tumor cell apoptosis.

Original languageEnglish (US)
Pages (from-to)1663-1673
Number of pages11
JournalJournal of Cellular Physiology
Issue number2
StatePublished - Feb 1 2020


  • apoptosis
  • autophagy
  • bone
  • oral squamous cell carcinoma

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cell Biology


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