title: ABL regulation by AXL promotes cisplatin resistance in esophageal cancer.
abstract: Esophageal adenocarcinoma (EAC) is characterized by resistance to chemotherapy and poor outcome. Although cisplatin (CDDP) has been used as a first-line therapy in patients with EAC, resistance remains a major clinical problem. The AXL receptor tyrosine kinase, originally isolated as a transforming gene from leukemia, is overexpressed in several solid tumors. Herein, we assessed AXL protein expression in human EACs and examined its role in CDDP resistance in human EAC cells. AXL overexpression was detected in more than 50% of tumors examined. Elevating AXL in nonoverexpressing cells doubled the CDDP IC(50) and increased cell survival three-fold, while attenuating AXL in overexpressing cells reduced survival two-fold. The effects of AXL modulation on cell survival were associated with changes in cellular and molecular markers of apoptosis. Mechanistic investigations revealed that AXL blocked CDDP-induced activation of endogenous p73β (TP73), reducing its protein half-life, and inhibited CDDP-induced levels of p-c-ABL(Y412) and p-p73β(Y99). These changes were associated with a disruption of c-ABL/p73β protein interactions due to association with c-ABL in the cytoplasm, thereby blocking nuclear accumulation of c-ABL and phosphorylation of p73β in response to DNA damage. Together, our results establish that AXL promotes CDDP resistance in esophageal adenocarcinoma and argue that therapeutic targeting of AXL may sensitize these cancers to DNA-damaging drugs.
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Hong
authors.forename: Dunfa
authors.initials: D
authors.lastname: Peng
authors.forename: Zheng
authors.initials: Z
authors.lastname: Chen
authors.forename: Vikas
authors.initials: V
authors.lastname: Sehdev
authors.forename: Abbes
authors.initials: A
authors.lastname: Belkhiri
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D004938:Esophageal Neoplasms / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D000970:Antineoplastic Agents; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D016315:Proto-Oncogene Proteins c-abl; D002945:Cisplatin; D000094963:Axl Receptor Tyrosine Kinase; C000722289:AXL protein, human