The Role of c‑Jun Signaling in Cytidine Analog-Induced Cell Death in Melanoma

Melanoma stands as an increasingly pressing health concern.
Enhanced
mitochondrial metabolism has been reported in melanoma cells that
survived treatment with traditional therapeutics, including cytidine
analogs like gemcitabine (GEM). These findings suggest that chemotherapeutic
drugs may play dual roles in promoting both cell survival and cell
death, although the underlying mechanisms require further investigation.
Herein, we conducted proteomics analysis on GEM-treated melanoma cells
and found a drug-induced activation of DNA damage response and apoptosis,
along with cell cycle arrest. Additionally, GEM treatment significantly
altered protein networks related to mitochondrial ribosomal activity,
the electron transport chain, and translation. Furthermore, we reported
an upregulation of the JNK/c-Jun network in connection with the apoptotic
proteins. Co-treatment with a Jun N-terminal Kinase (JNK) inhibitor,
JNK-IN-8 (JNKi), significantly increased cell survival,
suggesting the involvement of c-Jun signaling in GEM-induced cell
death. Additionally, proteomics analysis revealed that JNKi downregulated apoptosis in cotreated cells, highlighting the potential
role of the JNK/c-Jun network inhibition in chemotherapeutic tolerance.
Collectively, our findings bridge gaps in understanding how melanoma
cells respond to cytidine analogs by demonstrating the multifaceted
effects of these agents in (1) inducing JNK-mediated apoptotic cell
death and (2) promoting a state of cell cycle inhibition.