HSP90 is a promising target in gemcitabine and 5-fluorouracil resistant pancreatic cancer

Abstract

Chemotherapy (CT) options in pancreatic cancer (PC) are limited to gemcitabine and 5-fluorouracil (5-FU). Several identified molecular targets in PC represent client proteins of HSP90. HSP90 is a promising target since it interferes with many oncogenic signaling pathways simultaneously. The aim of this study was to evaluate the efficacy of different HSP90 inhibitors in gemcitabine and 5-FU resistant PC. PC cell lines 5061, 5072 and 5156 were isolated and brought in to culture from patients being operated at our institution. L3.6pl cell line served as a control. Anti-proliferative efficacy of three different HSP90 inhibitors (17-AAG, 17-DMAG and 17-AEPGA) was evaluated by the MTT assay. Alterations in signaling pathway effectors and apoptosis upon HSP90 inhibition were determined by western blot analysis and annexin V/PI staining. The cell lines 5061, 5072 and 5156 were resistant to gemcitabine and 5-FU. In contrast 17-AAG and the water-soluble derivates 17-DMAG and 17-AEPGA displayed high anti-proliferative activity in all tested cell lines. The calculated IC was below 1 µM. Highly significant down regulation of epidermal-growth-factor-receptor, insulin-like-growth-factor-receptor-1, AKT and MAPK reflected the intracellular molecular signaling-network disruption. Furthermore, besides HSP70 also HSP27 was upregulated in all cell lines. Apoptosis occurred early under HSP90 inhibition and was determined by annexin V/PI staining and CASPASE-3 and PARP assay. In contrast, gemcitabine treated cells did not show any apoptosis. HSP90 inhibition disrupts multiple signaling cascades in gemcitabine and 5-FU resistant PC simultaneously and promotes cancer cell apoptosis. Watersoluble 17-DMAG is equally effective as 17-AAG. HSP27, besides HSP70, may represent an effective response marker of successful HSP90 inhibition.

Inhibition of HSP90 overcomes resistance to chemotherapy and radiotherapy in pancreatic cancer

“…Our findings agree with previously published data by Ghadban et al showing that the inhibition of HSP90 in gemcitabine and 5‐FU resistant pancreatic cell lines can induce apoptosis. While HSP90 inhibitors could impact different cellular pathways, data in the present report suggests that HSP90 inhibition enhances the impact of 5‐FU and IR via modulation of HIF‐1α. Indeed, inhibiting HSP90 is known to affect DNA repair pathways sensitizing cancer cells to radiation .…”

SUV420H2 is an epigenetic regulator of epithelial/mesenchymal states in pancreatic cancer

“…Finally, mesenchymal cancer cells are universally more resistant to anticancer drugs than their epithelial counterparts ( Singh and Settleman, 2010 ). SUV420H2 knockdown rendered mesenchymal pancreatic cancer cells significantly more sensitive to gemcitabine and 5-fluorouracil, two of the most commonly used chemotherapies in human PDAC ( Ghadban et al, 2017 ; Fig. 4 D and Fig.…”

Heat Shock Proteins: Agents of Cancer Development and Therapeutic Targets in Anti-Cancer Therapy

“…Lung and ovarian cancer, osteosarcoma Induction of chemoresistance to cisplatin and 5-FU [105][106][107][108] Ovarian cancer Enhancement of drug sensitivity to cisplatin by increasing mitochondrial cytochrome c release via inhibition of Mortalin [109] Colorectal and ovarian cancer Acquirement of 5-FU resistance via regulation of PI3K/AKT/mTOR and c-Src/LSF/TS signal by GRP78 [108,110] Cervical cancer Induction of apoptosis by regulating mitochondrial related proteins via GRP78 knockdown [111] Osteosarcoma Decrease of HSP70 expression by miR-223, deactivation of JNK/JUN signal, and enhancement of cisplatin sensitivity [106] Non-small cell lung cancer Promotion of cellular resistance to EGFR tyrosine inhibitors by enhancing gene mutation and tumor heterogeneity via inhibition of HSP70 [112] HSP90 Osteosarcoma Induction of chemoresistance by inducing autophagy via PI3K/AKT/mTOR pathway and inhibiting of apoptosis via JNK/p38 pathway [113] Colon cancer Acquirement of drug resistance by activating HSP90 client proteins, such as EGFR, IGF-IR, and Src [114] Ovarian cancer Regulation of various drug resistant genes, such as LRP, GST-π, p53, bcl-2, survivin, ERCC1, XRCC1, BRCA1 and BRCA2 [115] Pancreatic cancer Induction of drug resistance to 5-FU and gemcitabine by regulating AKT and MAPK and enhancing apoptosis via inhibition of HSP90 [116] Breast and gastric cancer AUY-022 (HSP90 inhibitor), increased effects of lapatinib via inhibition of HER2 and AKT pathway [117] HSP27 is associated with chemoresistance and poor prognosis in multiple cancers, including gastric, liver, prostate, lung, and colorectal cancers [16]. HSP27 enhances multidrug-resistance in squamous cell carcinoma of tongue (SCCT) through hyperactivation of NF-κB.…”