Oyama Keisuke, Iwagami Yoshifumi, Kobayashi Shogo, Sasaki Kazuki, Yamada Daisaku, Tomimaru Yoshito, Noda Takehiro, Asaoka Tadafumi, Takahashi Hidenori, Tanemura Masahiro, Doki Yuichiro, Eguchi Hidetoshi
Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
Department of Surgery, Osaka Police Hospital, Osaka, Japan.
Int J Cancer. 2024 Mar 1;154(5):912-925. doi: 10.1002/ijc.34725. Epub 2023 Sep 12.
Insufficient cancer treatment can induce senescent cancer cell formation and treatment resistance. The characteristics of induced senescent cancer (iSnCa) cells remain unclear. Pancreatic ductal adenocarcinoma (PDAC) has a low and nondurable response rate to current treatments. Our study aimed to analyze the properties of iSnCa cells and the relationship between cellular senescence and prognosis in PDAC. We evaluated the characteristics of gemcitabine-induced senescent cancer cells and the effect of senescence-associated secretory phenotype (SASP) factors released by iSnCa cells on surrounding PDAC cells. The relationship between cellular senescence and the prognosis was investigated in 50 patients with PDAC treated with gemcitabine-based neoadjuvant chemotherapy. Exposure to 5 ng/mL gemcitabine-induced senescence, decreased proliferation and increased senescence-associated β-galactosidase-cell staining without cell death in PDAC cells; the expression of glutaminase1 (GLS1) and SASP factors also increased and caused epithelial-mesenchymal transition in surrounding PDAC cells. iSnCa cells were selectively removed by the GLS1 inhibitor bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES) through apoptosis induction. Cellular senescence was induced in PDAC cells via insufficient gemcitabine in subcutaneous tumor model mice. GLS1 expression was an independent prognostic factor in patients with PDAC who received gemcitabine-based neoadjuvant chemotherapy. This is the first study to identify the relationship between senescence and GLS1 in PDAC. Low-dose gemcitabine-induced senescence and increased GLS1 expression were observed in PDAC cells. Cellular senescence may contribute to treatment resistance of PDAC, hence targeting GLS1 in iSnCa cells may improve the therapeutic effect.
癌症治疗不足可诱导衰老癌细胞形成并导致治疗抵抗。诱导性衰老癌细胞（iSnCa）的特征尚不清楚。胰腺导管腺癌（PDAC）对当前治疗的反应率低且不持久。我们的研究旨在分析iSnCa细胞的特性以及细胞衰老与PDAC预后之间的关系。我们评估了吉西他滨诱导的衰老癌细胞的特征以及iSnCa细胞释放的衰老相关分泌表型（SASP）因子对周围PDAC细胞的影响。在50例接受以吉西他滨为基础的新辅助化疗的PDAC患者中，研究了细胞衰老与预后之间的关系。暴露于5 ng/mL吉西他滨可诱导衰老，降低PDAC细胞的增殖并增加衰老相关β-半乳糖苷酶细胞染色，且无细胞死亡；谷氨酰胺酶1（GLS1）和SASP因子的表达也增加，并导致周围PDAC细胞发生上皮-间质转化。GLS1抑制剂双-2-（5-苯乙酰氨基-1,2,4-噻二唑-2-基）乙基硫醚（BPTES）通过诱导凋亡选择性清除iSnCa细胞。在皮下肿瘤模型小鼠中，通过不足量的吉西他滨在PDAC细胞中诱导细胞衰老。GLS1表达是接受以吉西他滨为基础的新辅助化疗的PDAC患者的独立预后因素。这是第一项确定PDAC中衰老与GLS1之间关系的研究。在PDAC细胞中观察到低剂量吉西他滨诱导衰老并增加GLS1表达。细胞衰老可能导致PDAC的治疗抵抗，因此靶向iSnCa细胞中的GLS1可能会提高治疗效果。
