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Tramadol Triggers Paraptotic Cell Death through ATF4 in Breast Cancer Cells

ABSTRACT: Breast cancer treatment has significantly improved, achieving a five-year survival rate of 90%. However, 30% to 50% of survivors continue to suffer from persistent pain, a common long-term side effect. Tramadol, an analgesic often prescribed for postsurgical pain, has recently been shown to have anticancer effects on breast cancer cells. The use of tramadol in postoperative care has been associated with reduced recurrence and improved survival rates, but the mechanisms involved in its anticancer activity are not fully understood. This study explored how tramadol induces paraptosis, a form of nonapoptotic cell death, by focusing on endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) pathways in breast cancer cells. The findings revealed that tramadol treatment increased ROS levels, triggering ER stress and activating the p-eIF2α/ATF4/CHOP signaling axis. This stress response led to cytoplasmic vacuolization and mitochondrial dysfunction, both of which are key features of paraptosis. Inhibiting ROS production or blocking the ATF4 pathway reduced tramadol-induced paraptosis, confirming the critical role of these mechanisms in breast cancer cells. In summary, tramadol induces paraptosis in breast cancer cells by activating ROS and ER stress, offering potential insight into its anticancer effects. These findings could have implications for improving both pain management and cancer treatment outcomes in breast cancer patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE282008 | GEO | 2025/11/15

REPOSITORIES: GEO

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Project description:Background: Paraptosis is a programmed cell death characterized by cytoplasmic vacuolation, which has been used as an alternative cell death method for cancer treatment and is associated with cancer resistance. However, the mechanisms underlying the progression of paraptosis in cancer cells are largely unknown. Methods: Paraptosis-inducing agents, CPYPP, cyclosporin, and curcumin, were utilized to investigate the underlying mechanism of paraptosis. Next-generation sequencing and liquid chromatography-mass spectrometry analysis revealed significant changes in gene and protein expressions. Pharmacological and genetic approaches were employed to elucidate the transcriptional events related to paraptosis. The xenograft mouse models were employed to evaluate the potential of paraptosis as an anti-cancer strategy. Results: CPYPP, cyclosporin A, and curcumin induced cytoplasmic vacuolization and triggered paraptosis in cancer cells. The paraptotic program involved reactive oxygen species (ROS) provocation and the activation of proteostatic dynamics, leading to transcriptional activation associated with redox homeostasis and proteostasis. Both pharmacological and genetic approaches suggested that cyclin-dependent kinase (CDK) 7/9 drive paraptotic progression in a mutually-dependent manner with heat shock proteins (HSPs). Proteostatic stress, such as accumulated cysteine-thiols, HSPs, ubiquitin-proteasome system, endoplasmic reticulum stress, and unfolded protein response, as well as ROS provocation primarily within the nucleus, enforced CDK7/CDK9–Rpb1 (RNAPII subunit B1) activation by potentiating its interaction with HSPs and protein kinase R (PKR) in a forward loop, amplifying transcriptional regulation and thereby exacerbating proteotoxicity leading to initiate paraptosis. A xenograft mouse model with OECM-1 cells further confirmed the induction of paraptosis against tumor growth. Conclusions We propose a novel regulatory paradigm in which the activation of CDK7/CDK9–Rpb1 by nuclear proteostatic stress mediates transcriptional regulation to prime cancer cell paraptosis.

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Tramadol Triggers Paraptotic Cell Death through ATF4 in Breast Cancer Cells

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