Silencing of NRF2 Reduces the Expression of ALDH1A1 and ALDH3A1 and Sensitizes to 5-FU in Pancreatic Cancer Cells

Abstract

Pancreatic cancer remains an intractable cancer with a poor five-year survival rate, which requires new therapeutic modalities based on the biology of pancreatic oncogenesis. Nuclear factor E2 related factor-2 (NRF2), a key cytoprotective nuclear transcription factor, regulates antioxidant production, reduction, detoxification and drug efflux proteins. It also plays an essential role in cell homeostasis, cell proliferation and resistance to chemotherapy. We aimed to evaluate the possibility that modulation of NRF2 expression could be effective in the treatment of pancreatic cancer cells. We investigated whether the depletion of NRF2 by using small interfering RNAs (siRNAs) is effective in the expression of biomarkers of pancreatic cancer stemness such as aldehyde dehydrogenase 1 family, member A1 (ALDH1A1) and aldehyde dehydrogenase 3 family, member A1 (ALDH3A1). NRF2 knockdown markedly reduced the expression of NRF2 and glutamate-cysteine ligase catalytic subunit (GCLC) in cell lines established from pancreatic cancers. NRF2 silencing also decreased the ALDH1A1 and ALDH3A1 expression. Furthermore, this NRF2 depletion enhanced the antiproliferative effects of the chemotherapeutic agent, 5-fluorouracil (5-FU) in pancreatic cancer cells.

Proteome Profiling of Primary Pancreatic Ductal Adenocarcinomas Undergoing Additive Chemoradiation Link ALDH1A1 to Early Local Recurrence and Chemoradiation Resistance

“…ALDH1A1 has been implicated in cancer therapy resistance in various studies [50], [51], [52], [53], [54], [55], [56]. ALDH1A1 is a cytosolic enzyme and a member of the ALDH family of enzymes.…”

Mutation of the gene encoding the circadian clock component PERIOD2 in oncogenic cells confers chemoresistance by up-regulating the Aldh3a1 gene

“…2D). High ALDH activity is often detected in cells with stemlike properties (26). Our previous study demonstrated that oncogene-transformed Per2 m/m cells have potent tumor formation ability (17).…”

F‑box proteins involved in cancer‑associated drug resistance (Review)

“…Nrf2 is controlled by two distinct β-TrCP recognition motifs in its Neh6 domain, one of which can be modulated by GSK-3 activity (83). Furthermore, overexpression of Nrf2, nuclear factor (erytheroid-derived-2)-like 2, increases resistance to the chemotherapeutic drug in breast cancer, acute myeloid leukemia and pancreatic cancer (84)(85)(86). However, the molecular mechanism between them remains further elucidated.…”

“…In multiple myeloma cell lines, DEP-domain containing mTOR-interacting protein (DEPTOR), another endogenous mTOR inhibitor, is inversely correlated with cell's responsiveness to anticancer drugs, such as rapamycin, velcade, paclintaxel, via modifying the mTOR pathway. The degradation of DEPTOR is mainly controlled by β-TrCP, which gives us a clue that the dysregulation of β-TrCP directly affects the response of patients to chemotherapeutic agents (86). Sp1, specificity protein 1, is another agent enhances temozolomide resistance in glioblastoma (87).…”