CYB5R3 functions as a tumor suppressor by inducing ER stress-mediated apoptosis in lung cancer cells via the PERK-ATF4 and IRE1α-JNK pathways.

Im, Joo-Young; Kim, Soo Jin; Park, Jong-Lyul; Han, Tae-Hee; Kim, Woo-il; Kim, Inhyub; Ko, Bomin; Chun, So-Young; Kang, Mi-Jung; Kim, Bo-Kyung; Jeon, Sol A.; Kim, Seon-Kyu; Ryu, Incheol; Kim, Seon-Young; Nam, Ki-Hoan; Hwang, Inah; Ban, Hyun Seung; Won, Misun

Cytochrome b5 reductase 3 (CYB5R3) is involved in various cellular metabolic processes, including fatty acid synthesis and drug metabolism. However, the role of CYB5R3 in cancer development remains poorly understood. Here, we show that CYB5R3 expression is downregulated in human lung cancer cell lines and tissues. Adenoviral overexpression of CYB5R3 suppresses lung cancer cell growth in vitro and in vivo. However, CYB5R3 deficiency promotes tumorigenesis and metastasis in mouse models. Transcriptome analysis revealed that apoptosis- and endoplasmic reticulum (ER) stress-related genes are upregulated in CYB5R3-overexpressing lung cancer cells. Metabolomic analysis revealed that CYB5R3 overexpression increased the production of nicotinamide adenine dinucleotide (NAD ) and oxidized glutathione (GSSG). Ectopic CYB5R3 is mainly localized in the ER, where CYB5R3-dependent ER stress signaling is induced via activation of protein kinase RNA-like ER kinase (PERK) and inositol-requiring enzyme 1 alpha (IRE1α). Moreover, NAD activates poly (ADP-ribose) polymerase16 (PARP16), an ER-resident protein, to promote ADP-ribosylation of PERK and IRE1α and induce ER stress. In addition, CYB5R3 induces the generation of reactive oxygen species and caspase-9-dependent intrinsic cell death. Our findings highlight the importance of CYB5R3 as a tumor suppressor for the development of CYB5R3-based therapeutics for lung cancer. The Role of CYB5R3 in Lung Cancer: From Metabolism to Therapeutics Lung cancer is the top cause of cancer-related deaths globally, with most patients having a form known as non-small cell lung cancer (NSCLC - a type of lung cancer that grows and spreads more slowly than other types). Despite progress in understanding the genetic shifts in lung cancer, diagnosing and treating this disease still pose challenges. This study focused on a protein named Cytochrome b5 reductase 3 (CYB5R3 - a protein involved in multiple biological functions, including energy production and fat metabolism). The research discovered that CYB5R3 presence is reduced in lung cancer and that an increase in CYB5R3 can cause cancer cells to die. This implies that CYB5R3 might act as a tumor suppressor (a gene that regulates cell division and prevents tumor formation) and could be a potential treatment target for lung cancer. "This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author."

Experimental & Molecular Medicine EMM, 2024, Vol 56, Issue 1, p235

1226-3613

Academic Journal

10.1038/s12276-024-01155-9