SMS1 and SMS2 differentially regulate platinum chemotherapy sensitivity in ovarian cancer cells

Altered platinum chemotherapy sensitivity is a major determinant of treatment outcome in ovarian cancer; however, the molecular mechanisms underlying adaptive chemotherapy responses remain incompletely understood. Sphingomyelin synthase 1 (SMS1) and sphingomyelin synthase 2 (SMS2), key enzymes involved in sphingomyelin biosynthesis, have been implicated in cancer biology, but their roles in platinum chemotherapy response remain unclear.

SMS1 and SMS2 expression was evaluated in ovarian cancer cells following chemotherapy exposure. Gain- and loss-of-function approaches were used to investigate their effects on cell proliferation, apoptosis, and chemotherapy sensitivity, while biochemical assays were performed to explore underlying mechanisms. Cisplatin selectively induced SMS1, but not SMS2, expression at both mRNA and protein levels in a dose- and time-dependent manner. Silencing of either SMS1 or SMS2 inhibited cell growth, promoted apoptosis, and enhanced sensitivity to cisplatin and paclitaxel. However, only SMS1 overexpression consistently protected cells against cisplatin- and paclitaxel-induced apoptosis. Mechanistically, SMS1 depletion caused lysosomal impairment, increased lipid peroxidation, and enhanced lysosome-associated oxidative injury, whereas SMS2 depletion induced oxidative stress-related alterations without a clearly defined dominant downstream mechanism. Importantly, multiple platinum agents, including cisplatin, carboplatin, and oxaliplatin, selectively induced SMS1 expression, and SMS1 depletion enhanced sensitivity to platinum-based chemotherapy. Clinical survival analysis further revealed that high SMS1 expression was associated with poorer outcomes, particularly in patients receiving Taxol plus platinum-based chemotherapy.

SMS1 and SMS2 differentially regulate platinum chemotherapy sensitivity in ovarian cancer cells. SMS1 functions as a platinum-induced adaptive resistance factor by maintaining lysosomal homeostasis and supporting tumor cell survival. Disrupting SMS1-mediated adaptation may represent a potential strategy to enhance platinum chemotherapy efficacy. Although SMS2 contributes to chemotherapy response, its downstream mechanisms remain to be further elucidated.