Integrative analyzes revealed roles of G6PD in resistance to cisplatin via the redox system

Spheroids derived from serous ovarian carcinoma serve as convenient surrogates for assessing patient sensitivity to chemotherapy. (Scale: 50 µm). Credit: University of Niigata

Three-dimensional (3D) culture approaches help probe for traits associated with cancer stem cells (CSCs), drug resistance, and cell heterogeneity ex vivo. For example, culturing organoid-based clinical cancer samples can reiterate the histology and landscape of corresponding tumor mutations, and the creation of these organoids are suitable surrogates for tumors in vivo. Obviously, the chemosensitivity of organoids often reflects the clinical response of patients, and panels of well-known organoids are used to systematically examine sensitivity to chemotherapeutic agents. Therefore, understanding the molecular basis of their differential responses to chemotherapeutic agents will likely lead to better precision in personalized cancer therapy.

Dr Kaoru Yamawaki, Dr Takayuki Enomoto and colleagues at the Department of Obstetrics and Gynecology, Faculty of Medicine, Niigata University, Niigata, Japan, and Dr Koji Okamoto and his team at the Division of Cancer Differentiation, National Cancer Center Research Institute, Tokyo, Japan observed that spheroid screening might be suitable for identifying effective therapeutic compounds for treating cancers otherwise refractory to treatment.

Although standard chemotherapy, which combines compounds based on taxane and platinum, is initially effective for many patients with ovarian cancer, most of them eventually develop recurrent cancers. In addition, in advanced cases (stage III or IV),> 70% of patients experience recurrence within five years of standard treatment. Because platinum sensitivity is a major determinant of prognosis, there is a serious medical need to understand the molecular basis of platinum drug resistance in ovarian cancer.

Since the spheroid exhibited distinct intertumoral heterogeneity associated with chemosensitivity to platinum-based compounds, Dr. Yamawaki and his colleagues exploited the established spheroids to compare cisplatin chemosensitivity and gene expression profiles to better understand the molecular basis of such heterogeneity and to systematically examine the sensitivity to therapeutic compounds.

Statistical analyzes of cisplatin-resistant spheroids derived from ovarian cancer revealed that drug resistance was related to significantly elevated expression of genes associated with activation of glutathione-mediated redox metabolism. Many enzymes involved in glutathione-mediated redox systems require NADPH, the production of which is largely attributed to glucose-6-phosphate dehydrogenase (G6PD), a guardian enzyme of the pentose phosphate pathway. The generation of NADPH by G6PD is critical for redox homeostasis and thus contributes to the adaptation of cancer cells against oxidative stress. In the present study, they found that drug-resistant spheroids expressed high levels of G6PD and NADPH-dependent redox genes, suggesting that G6PD plays a crucial role in resistance to cisplatin by affecting several enzymes that regulate the redox system. In addition, analyzes of clinical samples showed that G6PD expression was significantly associated with a poor prognosis suggesting that resistance to cisplatin in ovarian cancer is related to high expression of redox proteins.

Overall, the data presented by Dr. Yamawaki and his associates underscore the importance of the integrative approach that uses patient-derived spheroids to define the non-genetic basis of drug resistance in cancer. Dr Yamawaki said: “We have established a panel of spheroids derived from clinical samples of ovarian cancer and used them as a platform to systematically interrogate chemosensitivity against therapeutic compounds. compounds based on compounds, we investigated molecular profiling associated with chemosensitivity to cisplatin to understand the molecular basis of heterogeneity. metabolism via the production of NADPH. ”

In addition, they believe their findings contribute to conceptual advancement by demonstrating the clinical importance of the integrative approach using patient-derived spheroids to understand chemoresistance in other types of cancer refractory to primary chemotherapy.

‘Automated’ Microscopy Identifies Predictor of Chemotherapy Resistance in Ovarian Cancer Patients

More information:
Kaoru Yamawaki et al, Integrative analyzes of gene expression and chemosensitivity of ovarian cancer spheroids derived from female patients link redox metabolism induced by G6PD to chemoresistance to cisplatin, Cancer letters (2021). DOI: 10.1016 / j.canlet.2021.08.018

Provided by the University of Niigata

Quote: Integrative analyzes revealed roles of G6PD in resistance to cisplatin via the redox system (2021, October 7) retrieved October 7, 2021 from -roles-g6pd-cisplatin.html

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