DIM-C-pPhtBu induces lysosomal dysfunction and unfolded protein response - mediated cell death via excessive mitophagy

• Published in: Cancer letters Vol. 504; pp. 23 - 36
• Main Authors: Kang, Sung Un, Kim, Dae Ho, Lee, Yun Sang, Huang, Mei, Byeon, Hyung Kwon, Lee, Seong-Ho, Baek, Seung Joon, Kim, Chul-Ho
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 28.04.2021; Elsevier Limited
• Subjects: 3,3′-diindolylmethane (DIM); Antibodies; Apoptosis; Apoptosis-linked gene 2-interacting protein X (AIP1/Alix); Autophagy; Cancer therapies; Cell death; Chaperones; Cytotoxicity; Differentially expressed genes (DEGs); Double-stranded RNA; Double-stranded RNA-Activated protein kinase-like ER kinase (PERK); eIF-2 kinase; Endoplasmic reticulum; Endoplasmic reticulum stress; Flow cytometry; Gene expression; Head & neck cancer; HNC (Head and neck cancer); Homeostasis; Kinases; Localization; Membrane proteins; Microscopy; Mitochondria; Mitophagy; Oxidative stress; Protein folding; Protein kinase R; Proteins; Reagents; Software; Transcription; Xenografts; United Kingdom > UK; United States > US; Switzerland; Baltimore Maryland; 3,3′-diindolylmethane (DIM); Double-stranded RNA-Activated protein kinase-like ER kinase (PERK); Apoptosis-linked gene 2-interacting protein X (AIP1/Alix); Differentially expressed genes (DEGs); HNC (Head and neck cancer); Endoplasmic reticulum stress
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2021.01.005

Despite technological advances in cancer treatment, the survival rate of patients with head and neck cancer (HNC) has not improved significantly. Many studies have shown that endoplasmic reticulum (ER) stress-related signals are associated with mitochondrial damage and that these signals determine whether cells maintain homeostasis or activate cell death programs. The unfolded protein response (UPR) is regulated by ER membrane proteins such as double-stranded RNA-activated protein kinase R(PKR)-like ER kinase (PERK), which directly activate transcription of chaperones or genes that function in redox homeostasis, protein secretion, or cell death programs. In this study, we focused on the role of mitophagy and ER stress-mediated cell death induced by DIM-C-pPhtBu in HNC cancer. We found that DIM-C-pPhtBu, a compound that activates ER stress in many cancers, induced lysosomal dysfunction, excessive mitophagy, and cell death in HNC cells. Moreover, DIM-C-pPhtBu strongly inhibited HNC progression in a xenograft model by altering mitophagy related protein expression. Taken together, the results demonstrate that DIM-C-pPhtBu induces excessive mitophagy and eventually UPR-mediated cell death in HNC cells, suggesting that new anti-cancer drugs could be developed based on the connection between mitophagy and cancer cell death. •DIM-C-pPhtBu induces mitophagy and ER stress in a ROS dependent manner.•Excessive mitophagy induces caspase‐independent cell death due to unfolded protein response.•DIM-C-pPhtBu induces abnormal lysosome activity and accumulation of autophagosome.•PERK-mediated unfolded protein response may play an important role in DIM-C-pPhtBu-induced mitophagy and cell death.