Mucin 4 Confers Gemcitabine Resistance and an Unfavorable Prognosis in Patients with Cholangiocarcinoma via AKT Activation

Abstract

Cholangiocarcinoma (CCA) exhibits aggressive biological behavior and a poor prognosis. Gemcitabine (GEM)-based chemotherapy is the first-line chemotherapy for advanced CCA but has a response rate of only 20-30%. Therefore, investigating treatments to overcome GEM resistance in advanced CCA is crucial. Among mucin (MUC) family members, MUC4 showed the greatest increase in the resistant versus parental sublines. MUC4 was upregulated in whole-cell lysates and conditioned media from gemcitabine-resistant (GR) CCA sublines. MUC4 mediated GEM resistance by activating AKT signaling in GR CCA cells. The MUC4-AKT axis induced BAX S184 phosphorylation to inhibit apoptosis and downregulated GEM transporter human equilibrative nucleoside transporter 1 (hENT1) expression. The combination of AKT inhibitors and GEM or afatinib overcame GEM resistance in CCA. In vivo, capivasertib (an AKT inhibitor) increased GEM sensitivity in GR cells. MUC4 promoted EGFR and HER2 activation to mediate GEM resistance. Finally, MUC4 expression in patient plasma correlated with MUC4 expression. Paraffin-embedded specimens from non-responders expressed significantly more MUC4 than did those from responders, and this upregulation was associated with poor progression-free survival and overall survival. In GR CCA, high MUC4 expression promotes sustained EGFR/HER2 signaling and AKT activation. The combination of AKT inhibitors with GEM or afatinib might overcome GEM resistance.

PLK1 and its substrate MISP facilitate intrahepatic cholangiocarcinoma progression by promoting lymphatic invasion and impairing E-cadherin adherens junctions

“…6D, E ), which may result from the depletion of PLK1 or MISP-induced mitotic arrest [ 29 , 51 ]. In vivo, mouse iCCA AKP-M1 cells [ 44 ] were injected into the left lobes of the livers of C57BL/6J mice. Treatment with the PLK1 inhibitor volasertib (25 mg/kg) suppressed tumor growth (Fig.…”

“…Human dermal lymphatic endothelial cells (HDLECs) were purchased from PromoCell (C-12217, Heidelberg, Germany). Mouse CCA AKP-M1 cells were previously described [ 44 ]. RBE cells, HuCCT1 cells, and HuCCT1-derived sublines (N1, N2, N3, and N4) were grown in RPMI medium supplemented with 10% fetal bovine serum (FBS) and penicillin‒streptomycin.…”

“…All procedures were conducted according to the institutional animal welfare guidelines of Chang Gung Memorial Hospital. The sample size was estimated from previous studies in tumor-bearing mice [ 44 ]. BALB/c nude mice were purchased from BioLASCO Taiwan Co., Ltd. HuCCT1 cells (5 × 10 6 ) were injected into the subcutaneous tissue of BALB / c nude mice.…”

Programmed Cell Death Pathways in Cholangiocarcinoma: Opportunities for Targeted Therapy

“…Several somatic mutations have been identified in CCA affecting genes involved in cell fate and differentiation, proliferation, survival, and maintenance of genomic integrity [15]. According to this, emerging evidence suggests that the dysregulation of programmed cell death pathways, including apoptosis, ferroptosis, pyroptosis and necroptosis, plays a crucial role in CCA development and progression [22,23]. Several molecular mechanisms underlying the resistance to cell death have been identified in CCA, including the aberrant expression of apoptosis and necroptosis regulators, dysregulated ferroptosis, and altered metabolic pathways.…”