Division of Gastroenterological, Hepato-Biliary-Pancreatic, Transplantation and Pediatric Surgery, Department of Surgery, Shinshu University School of Medicine, Matsumoto, Japan.
Cancer Sci. 2023 Nov;114(11):4388-4400. doi: 10.1111/cas.15962. Epub 2023 Sep 12.
Pancreatic ductal adenocarcinoma has a particularly poor prognosis as it is often detected at an advanced stage and acquires resistance to chemotherapy early during its course. Stress adaptations by mitochondria, such as metabolic plasticity and regulation of apoptosis, promote cancer cell survival; however, the relationship between mitochondrial dynamics and chemoresistance in pancreatic ductal adenocarcinoma remains unclear. We here established human pancreatic cancer cell lines resistant to gemcitabine from MIA PaCa-2 and Panc1 cells. We compared the cells before and after the acquisition of gemcitabine resistance to investigate the mitochondrial dynamics and protein expression that contribute to this resistance. The mitochondrial number increased in gemcitabine-resistant cells after resistance acquisition, accompanied by a decrease in mitochondrial fission 1 protein, which induces peripheral mitosis, leading to mitophagy. An increase in the number of mitochondria promoted oxidative phosphorylation and increased anti-apoptotic protein expression. Additionally, enhanced oxidative phosphorylation decreased the AMP/ATP ratio and suppressed AMPK activity, resulting in the activation of the HSF1-heat shock protein pathway, which is required for environmental stress tolerance. Synergistic effects observed with BCL2 family or HSF1 inhibition in combination with gemcitabine suggested that the upregulated expression of apoptosis-related proteins caused by the mitochondrial increase may contribute to gemcitabine resistance. The combination of gemcitabine with BCL2 or HSF1 inhibitors may represent a new therapeutic strategy for the treatment of acquired gemcitabine resistance in pancreatic ductal adenocarcinoma.
胰腺导管腺癌预后尤其差，因为它通常在晚期被发现，并在其病程中早期对化疗产生耐药性。线粒体的应激适应，如代谢可塑性和凋亡调节，促进癌细胞存活；然而，胰腺导管腺癌中线粒体动力学与化疗耐药性之间的关系尚不清楚。我们在这里从 MIA PaCa-2 和 Panc1 细胞中建立了对吉西他滨耐药的人胰腺癌细胞系。我们比较了获得吉西他滨耐药前后的细胞，以研究有助于这种耐药性的线粒体动力学和蛋白表达。在获得吉西他滨耐药后，耐药细胞中线粒体数量增加，同时线粒体分裂蛋白 1 减少，这会诱导外周有丝分裂，导致自噬。线粒体数量的增加促进了氧化磷酸化，增加了抗凋亡蛋白的表达。此外，增强的氧化磷酸化降低了 AMP/ATP 比值，抑制了 AMPK 活性，导致 HSF1-热休克蛋白通路的激活，这对于环境应激耐受是必需的。BCL2 家族或 HSF1 抑制剂与吉西他滨联合使用时观察到协同作用表明，线粒体增加引起的凋亡相关蛋白的上调可能导致吉西他滨耐药。吉西他滨与 BCL2 或 HSF1 抑制剂的联合应用可能代表治疗胰腺导管腺癌获得性吉西他滨耐药的一种新的治疗策略。
