title: Targeting Hedgehog signaling pathway and autophagy overcomes drug resistance of BCR-ABL-positive chronic myeloid leukemia.
abstract: The frontline tyrosine kinase inhibitor (TKI) imatinib has revolutionized the treatment of patients with chronic myeloid leukemia (CML). However, drug resistance is the major clinical challenge in the treatment of CML. The Hedgehog (Hh) signaling pathway and autophagy are both related to tumorigenesis, cancer therapy, and drug resistance. This study was conducted to explore whether the Hh pathway could regulate autophagy in CML cells and whether simultaneously regulating the Hh pathway and autophagy could induce cell death of drug-sensitive or -resistant BCR-ABL(+) CML cells. Our results indicated that pharmacological or genetic inhibition of Hh pathway could markedly induce autophagy in BCR-ABL(+) CML cells. Autophagic inhibitors or ATG5 and ATG7 silencing could significantly enhance CML cell death induced by Hh pathway suppression. Based on the above findings, our study demonstrated that simultaneously inhibiting the Hh pathway and autophagy could markedly reduce cell viability and induce apoptosis of imatinib-sensitive or -resistant BCR-ABL(+) cells. Moreover, this combination had little cytotoxicity in human peripheral blood mononuclear cells (PBMCs). Furthermore, this combined strategy was related to PARP cleavage, CASP3 and CASP9 cleavage, and inhibition of the BCR-ABL oncoprotein. In conclusion, this study indicated that simultaneously inhibiting the Hh pathway and autophagy could potently kill imatinib-sensitive or -resistant BCR-ABL(+) cells, providing a novel concept that simultaneously inhibiting the Hh pathway and autophagy might be a potent new strategy to overcome CML drug resistance.
authors.affiliation: a Department of Biosynthesis and Key Laboratory of Smart Drug Delivery; MOE; School of Pharmacy ; Fudan University ; Shanghai , China.
authors.forename: Xian
authors.initials: X
authors.lastname: Zeng
authors.forename: Hui
authors.initials: H
authors.lastname: Zhao
authors.forename: Yubin
authors.initials: Y
authors.lastname: Li
authors.forename: Jiajun
authors.initials: J
authors.lastname: Fan
authors.forename: Yun
authors.initials: Y
authors.lastname: Sun
authors.forename: Shaofei
authors.initials: S
authors.lastname: Wang
authors.forename: Ziyu
authors.initials: Z
authors.lastname: Wang
authors.forename: Ping
authors.initials: P
authors.lastname: Song
authors.forename: Dianwen
authors.initials: D
authors.lastname: Ju
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology*; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D053823:Hedgehog Proteins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl
keywords: ACTB, actin; AKT/protein kinase B, v-akt murine thymoma viral oncogene homolog; ATG, autophagy-related; BCC, basal cell carcinoma; BCR-ABL; BCR-ABL, breakpoint cluster region-ABL proto-oncogene, non-receptor tyrosine kinase; Bafi A1, bafilomycin A1; CASP, caspase; CML; CML, chronic myeloid leukemia; CQ, chloroquine; EIF4EBP1, eukaryotic translation initiation factor 4E binding protein 1; HCQ, hydroxychloroquine; Hh, Hedgehog; MAP1LC3B, microtubule-associated protein 1 light chain 3 β; MTOR, mechanistic target of rapamycin; PARP, poly (ADP-ribose) polymerase; PBMC, human peripheral blood mononuclear cell; PCR, polymerase chain reaction; RPS6KB, ribosomal protein S6 kinase, 70kDa; SQSTM1, sequestosome 1; TKI, tyrosine kinase inhibitor; apoptosis-related cysteine peptidase; autophagy; drug resistance; hedgehog pathway; siRNA, small interfering RNA; β