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

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

  • Int J Oral Sci. 2024 May 8;16(1):35. doi: 10.1038/s41368-024-00297-w.
Dexuan Zhuang 1 2,  Shuangshuang Wang 1,  Huiting Deng 2,  Yuxin Shi 2,  Chang Liu 1,  Xue Leng 1,  Qun Zhang 1,  Fuxiang Bai 1,  Bin Zheng 3,  Jing Guo 4 5,  Xunwei Wu 6 7
Affiliations

Affiliations

  • 1 School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, China.
  • 2 Engineering Laboratory for Biomaterials and Tissue Regeneration, Ningbo Stomatology Hospital, Savaid Stomatology School, Hangzhou Medical College, Ningbo, China.
  • 3 Cedars-Sinai Cancer Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • 4 School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, China. guojing@sdu.edu.cn.
  • 5 Engineering Laboratory for Biomaterials and Tissue Regeneration, Ningbo Stomatology Hospital, Savaid Stomatology School, Hangzhou Medical College, Ningbo, China. guojing@sdu.edu.cn.
  • 6 School and Hospital of Stomatology, Cheeloo College of Medicine, Shandong University & Shandong Key Laboratory of Oral Tissue Regeneration & Shandong Engineering Research Center of Dental Materials and Oral Tissue Regeneration & Shandong Provincial Clinical Research Center for Oral Diseases, Jinan, China. xunwei_2006@hotmail.com.
  • 7 Engineering Laboratory for Biomaterials and Tissue Regeneration, Ningbo Stomatology Hospital, Savaid Stomatology School, Hangzhou Medical College, Ningbo, China. xunwei_2006@hotmail.com.
PMID: 38719825 DOI: 10.1038/s41368-024-00297-w
Abstract

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.

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