RRAD, short for Ras-related associated with diabetes, is a member of the Ras-related GTPase superfamily. Primarily a cytosolic protein that acts in the plasma membrane, it is highly expressed in type 2 diabetes patients and serves as a biomarker for congestive heart failure. RRAD is involved in various cellular activities including cell division, motility, apoptosis, and energy metabolism through modulating tumor-related gene expression and interacting with multiple downstream effectors [1].

In cancer research, RRAD shows dual roles. In gastric and colorectal cancer, its inhibition reduces tumor cell proliferation, invasion, angiogenesis, and EMT marker expression, suggesting it could be a therapeutic target [2]. In papillary thyroid cancer, it is part of the NEAT1_2/RRAD/EHF positive feedback loop facilitating glycolysis [3]. In hepatocellular carcinoma, RRAD suppresses the Warburg effect by downregulating ACTG1, inhibiting cell proliferation and promoting apoptosis [4]. In lung cancer, it inhibits the Warburg effect via negative regulation of the NF-κB signaling [5]. In contrast, in glioblastoma, RRAD promotes EGFR-mediated STAT3 activation and temozolomide resistance [6]. In oral squamous cell carcinoma, downregulation of RRAD in the tumor margin enhances energy metabolism and tumor progression [7]. Also, RRAD is identified as a marker and negative regulator of cellular senescence, up-regulated in senescent cells and countering cellular senescence by reducing reactive oxygen species levels [8].

In summary, RRAD has diverse and context-dependent functions. In cancer, it can act as either an oncogene or a tumor suppressor. Its role in energy metabolism, cell proliferation, and apoptosis is crucial in understanding disease mechanisms. Studies on RRAD, especially through functional loss-of-function experiments, contribute to uncovering its complex roles in different diseases, providing potential therapeutic targets for cancers and insights into cellular senescence.

References:

1. Sun, Zhangyue, Li, Yongkang, Tan, Xiaolu, Xu, Liyan, Long, Lin. 2023. Friend or Foe: Regulation, Downstream Effectors of RRAD in Cancer. In Biomolecules, 13, . doi:10.3390/biom13030477. https://pubmed.ncbi.nlm.nih.gov/36979412/

2. Kim, Hee Kyung, Lee, Inkyoung, Kim, Seung Tae, Park, Joon Oh, Kang, Won Ki. 2019. RRAD expression in gastric and colorectal cancer with peritoneal carcinomatosis. In Scientific reports, 9, 19439. doi:10.1038/s41598-019-55767-7. https://pubmed.ncbi.nlm.nih.gov/31857616/

3. Sun, Wei, Wang, Zhiyuan, Qin, Yuan, He, Liang, Zhang, Hao. . NEAT1_2/RRAD/EHF Positive Feedback Loop Facilitates Aerobic Glycolysis in Papillary Thyroid Cancer Cells. In Endocrinology, 164, . doi:10.1210/endocr/bqad085. https://pubmed.ncbi.nlm.nih.gov/37279586/

4. Yan, Yingcai, Xu, Hao, Zhang, Linshi, Ge, Wenhao, Wang, Weilin. 2019. RRAD suppresses the Warburg effect by downregulating ACTG1 in hepatocellular carcinoma. In OncoTargets and therapy, 12, 1691-1703. doi:10.2147/OTT.S197844. https://pubmed.ncbi.nlm.nih.gov/30881024/

5. Liu, Juan, Zhang, Cen, Wu, Rui, Yang, Bo, Feng, Zhaohui. . RRAD inhibits the Warburg effect through negative regulation of the NF-κB signaling. In Oncotarget, 6, 14982-92. doi:. https://pubmed.ncbi.nlm.nih.gov/25893381/

6. Yeom, Seon-Yong, Nam, Do-Hyun, Park, Chaehwa. 2014. RRAD promotes EGFR-mediated STAT3 activation and induces temozolomide resistance of malignant glioblastoma. In Molecular cancer therapeutics, 13, 3049-61. doi:10.1158/1535-7163.MCT-14-0244. https://pubmed.ncbi.nlm.nih.gov/25313011/

7. Cheng, Aoming, Xu, Qiaoshi, Li, Bo, Han, Zhengxue, Feng, Zhien. 2024. The enhanced energy metabolism in the tumor margin mediated by RRAD promotes the progression of oral squamous cell carcinoma. In Cell death & disease, 15, 376. doi:10.1038/s41419-024-06759-7. https://pubmed.ncbi.nlm.nih.gov/38811531/

8. Wei, Zhao, Guo, Haiyang, Qin, Junchao, Gong, Yaoqin, Shao, Changshun. 2018. Pan-senescence transcriptome analysis identified RRAD as a marker and negative regulator of cellular senescence. In Free radical biology & medicine, 130, 267-277. doi:10.1016/j.freeradbiomed.2018.10.457. https://pubmed.ncbi.nlm.nih.gov/30391675/