Phenformin activates ER stress to promote autophagic cell death via NIBAN1 and DDIT4 in oral squamous cell carcinoma independent of AMPK

• Published in: International journal of oral science Vol. 16; no. 1; p. 35
• Main Authors: Zhuang, Dexuan, Wang, Shuangshuang, Deng, Huiting, Shi, Yuxin, Liu, Chang, Leng, Xue, Zhang, Qun, Bai, Fuxiang, Zheng, Bin, Guo, Jing, Wu, Xunwei
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.05.2024; Springer Nature B.V; Nature Publishing Group
• Subjects: 631/67/1665; 631/80/39; Activating transcription factor 4; AMP-Activated Protein Kinases - metabolism; Animals; Antitumor agents; Apoptosis; Apoptosis - drug effects; Apoptosis Regulatory Proteins - drug effects; Apoptosis Regulatory Proteins - metabolism; Autophagy; Autophagy - drug effects; Blotting, Western; Carcinoma, Squamous Cell - drug therapy; Cell death; Cell growth; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; Dentistry; DNA damage; Drug development; Endoplasmic reticulum; Endoplasmic Reticulum Stress - drug effects; Humans; Kinases; Medicine; Metformin; Mice; Mouth Neoplasms - drug therapy; Oral and Maxillofacial Surgery; Oral cancer; Oral carcinoma; Oral squamous cell carcinoma; Orthopedics; Phenformin - pharmacology; Phosphorylation; Protein kinase R; Squamous cell carcinoma; Surgical Orthopedics; Transcription activation; Transcription factors; Transcription Factors - drug effects; Transcription Factors - metabolism
• ISSN: 2049-3169; 1674-2818; 2049-3169
• DOI: 10.1038/s41368-024-00297-w

The efficient clinical treatment of oral squamous cell carcinoma (OSCC) is still a challenge that demands the development of effective new drugs. Phenformin has been shown to produce more potent anti-tumor activities than metformin on different tumors, however, not much is known about the influence of phenformin on OSCC cells. We found that phenformin suppresses OSCC cell proliferation, and promotes OSCC cell autophagy and apoptosis to significantly inhibit OSCC cell growth both in vivo and in vitro. RNA-seq analysis revealed that autophagy pathways were the main targets of phenformin and identified two new targets DDIT4 (DNA damage inducible transcript 4) and NIBAN1 (niban apoptosis regulator 1). We found that phenformin significantly induces the expression of both DDIT4 and NIBAN1 to promote OSCC autophagy. Further, the enhanced expression of DDIT4 and NIBAN1 elicited by phenformin was not blocked by the knockdown of AMPK but was suppressed by the knockdown of transcription factor ATF4 (activation transcription factor 4), which was induced by phenformin treatment in OSCC cells. Mechanistically, these results revealed that phenformin triggers endoplasmic reticulum (ER) stress to activate PERK (protein kinase R-like ER kinase), which phosphorylates the transitional initial factor eIF2, and the increased phosphorylation of eIF2 leads to the increased translation of ATF4. In summary, we discovered that phenformin induces its new targets DDIT4 and especially NIBAN1 to promote autophagic and apoptotic cell death to suppress OSCC cell growth. Our study supports the potential clinical utility of phenformin for OSCC treatment in the future.