Bladder cancer is a malignant tumour occurring from the urothelium of the bladder, and approximately 540,000 patients are newly diagnosed with bladder cancer, resulting in 190,000 deaths worldwide [1]. Tumours that invade the detrusor muscle are referred to as muscle-invasive bladder cancers (MIBC) and have an increased propensity to spread to lymph nodes and other organs [2]. A combined modality therapy such as total cystectomy and cisplatin (CDDP)-based chemotherapy is necessary for MIBC. However, MIBC frequently results in metastasis, and metastatic bladder cancer is often intractable with a median survival of ∼15 months even if it requires chemotherapy [3,4]. Some problems such as chemoresistance also persist in CDDP therapy [5]. Various CDDP-resistant factors of bladder cancer have been studied, but their clinical effects have been insufficiently explored. Therefore, a more effective chemotherapy regimen should be developed.

Although the mechanism of the anticancer effects of CDDP has not been fully elucidated, studies have demonstrated that CDDP causes cell death by increasing the generation of reactive oxygen species (ROS) [[6], [7], [8]]. The direct targets of ROS are cellular membrane glycerophospholipids. Polyunsaturated acids (PUFAs), which are compromised in glycerophospholipids, are susceptible to ROS damage and undergo a reaction called lipid peroxidation, generating various cytotoxic aldehydes such as 4-hydroxynonenal (HNE), malondialdehyde (MDA), and acrolein [9]. In addition, lipid peroxidation directly damages phospholipids, and oxidized phospholipids play an important role in cell death, including apoptosis, autophagy, and ferroptosis [10,11]. CDDP also induces ferroptosis, an iron-dependent and lipid peroxidation-mediated form of regulated cell death in normal kidneys [12].

Phospholipase A2s (PLA2s) function as detoxifying enzymes by hydrolyzing oxidized PUFA at the sn-2 position of glycerophospholipids. PLA2s are classified into three groups according to their cellular location and Ca2+-dependent enzymatic activity: cytosolic PLA2 (cPLA2), secretory PLA2 (sPLA2), and Ca2+-independent PLA2 (iPLA2) [13]. Among them, iPLA2β and iPLA2γ prevent cell death by removing oxidized fatty acids from oxidized phospholipids [[14], [15], [16]]. iPLA2β and iPLA2γ localize to the mitochondria, remove oxidized fatty acids from cardiolipin (CL), mitochondrial phospholipids, and regulate mitochondrial membrane remodeling [14,17,18]. iPLA2β suppresses ferroptosis upon ROS-induced stress by detoxifying peroxidized lipids in tumor cells [19,20]; however, no reports indicate that iPLA2γ is involved in ferroptosis. Considering these observations, we hypothesized that iPLA2s may play a key role in the cell death of CDDP-treated bladder cancer. In the present study, we first observed the expression of iPLA2γ in human bladder cancer tissues. We then investigated the involvement of iPLA2γ in CDDP-induced bladder cancer cell death via iPLA2γ knockdown.