Heteronemin, a Scalarane Sesterterpenoid, Activates Apoptosis and Non-Apoptotic Ferroptosis and Inhibits Cytoprotective Autophagy in Oral Cancer Cells

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Abstract
Oral squamous cell carcinoma (OSCC) ranks 16th worldwide as the most common type of malignancy in head and neck cancer globally, and addressing it has been an ongoing but difficult pursuit, as treatment resistance is commonly reported. Hence, employing multiple cell death pathways is an emerging strategy in overcoming treatment resistance in OSCC. We investigate here the effect of heteronemin, a marine sesterterpenoid isolated from sponges, for its anti-cancer potential, hypothesizing that it can induce non-apoptotic cell death pathways to overcome apoptosis-resistant cells and elucidate the underlying mechanisms involved. Our results show that heteronemin significantly kills cancer cells via the induction of the intrinsic apoptotic pathway. It also triggers ferroptosis, down-regulating glutathione peroxidase 4 (GPX4) and upregulating markers of lipid peroxidation such as 4-hydroxynonenal and malondialdehyde. We demonstrate that increasing reactive oxygen species generation plays a central role in triggering these pathways. ensuring the death of the cancer cells despite a compensation attempt via inducing autophagy and modulating Nrf2. Our study is the first to demonstrate the complex but interesting role of heteronemin in killing OSCC cells: inducing apoptosis and switching to ferroptosis as the cells attempt to survive. It also inhibits protective autophagy, leaving OSCC cells incapable of protecting themselves from imminent death. This complex mechanism adds to the existing knowledge on the mechanism of heteronemin as a strong therapeutic compound to treat OSCC cells.

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