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Golgi Acidification by NHE7 Regulates Cytosolic pH Homeostasis in Pancreatic Cancer Cells.
Galenkamp, KMO, Sosicka, P, Jung, M, Recouvreux, MV, Zhang, Y, Moldenhauer, MR, Brandi, G, Freeze, HH, Commisso, C
Cancer discovery. 2020;(6):822-835
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Abstract
Cancer cells reprogram their metabolism to meet elevated energy demands and favor glycolysis for energy production. This boost in glycolytic flux supports proliferation, but also generates acid in the form of hydrogen ions that must be eliminated from the cytoplasm to maintain the alkaline intracellular pH (pHi) associated with transformation. To cope with acid production, tumor cells employ ion transport systems, including the family of sodium-hydrogen exchangers (NHE). Here, we identify NHE7 as a novel regulator of pHi in pancreatic ductal adenocarcinoma (PDAC). We determine that NHE7 suppression causes alkalinization of the Golgi, leading to a buildup of cytosolic acid that diminishes tumor cell fitness mainly through the dysregulation of actin. Importantly, NHE7 knockdown in vivo leads to the abrogation of tumor growth. These results identify Golgi acidification as a mechanism to control pHi and point to the regulation of pHi as a possible therapeutic vulnerability in PDAC. SIGNIFICANCE NHE7 regulates cytosolic pH through Golgi acidification, which points to the Golgi as a "proton sink" for metabolic acid. Disruption of cytosolic pH homeostasis via NHE7 suppression compromises PDAC cell viability and tumor growth.See related commentary by Ward and DeNicola, p. 768.This article is highlighted in the In This Issue feature, p. 747.
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A Chinese Retrospective Multicenter Study of First-Line Chemotherapy for Advanced Pancreatic Cancer.
Cui, H, Guan, J, Deng, G, Yuan, J, Lou, C, Zhang, W, Zhou, A, Zhang, Y, Zhou, J, Dai, G
Medical science monitor : international medical journal of experimental and clinical research. 2020;:e927654
Abstract
BACKGROUND Pancreatic cancer (PC) is a common digestive system tumor. For patients with advanced pancreatic cancer (APC), chemotherapy is still the predominant treatment. However, no large-scale clinical studies have been done of it as first-line therapy for APC. The goal of the present study was to assess real-world outcomes with chemotherapy in that setting. MATERIAL AND METHODS We retrospectively analyzed data from 322 patients with APC who were treated with chemotherapy at 4 hospitals in different cities in China. The first-line regimens used were AS (nab-paclitaxel and S-1), AG (nab-paclitaxel and gemcitabine), and FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin). RESULTS Of the patients, 232 received AS, 79 received AG, and 11 received FOLFIRINOX. The median number of chemotherapy cycles was 5. The median overall survival (mOS) was 9 months and the median progression-free survival (mPFS) was 5 months. The AS, AG, and FOLFIRINOX regimens were associated with mOS rates of 9 months, 9 months, and 10 months, respectively. The mPFS rates for the AS, AG, and FOLFIRINOX regimens were 5, 4, and 5 months, respectively. The differences between the PFS rates for the regimens were statistically significant. The overall response rate (ORR) and overall disease control rate (DCR) for chemotherapy were 38% and 81.8%, respectively. The ORRs for the AS, AG, and FOLFIRINOX regimens were 46.9%, 18.7%, and 0%, respectively. The DCRs for the AS, AG and FOLFIRINOX regimens were 87.2%, 69.3%, and 63.6%, respectively. The differences between the ORRs and DCRs for the regimens were statistically significant. The incidences of grade 3/4 adverse events (AEs) associated with the AS, AG, and FOLFIRINOX regimens were 29.9%, 25%, and 36.4%, respectively. CONCLUSIONS The AS regimen was associated with a higher ORR and DCR than the other 2 regimens, with a lower rate of AEs.