EMAIL THIS PAGE TO A FRIEND

Oncotarget

KLF4-SQSTM1/p62-associated prosurvival autophagy contributes to carfilzomib resistance in multiple myeloma models.


PMID 26109433

Abstract

Multiple myeloma (MM) is an incurable clonal plasma cell malignancy. Because of a high rate of immunoglobulin synthesis, the endoplasmic reticulum of MM cells is subjected to elevated basal levels of stress. Consequently, proteasome inhibitors, which exacerbate this stress by inhibiting ubiquitin-proteasome-mediated protein degradation, are an important new class of chemotherapeutic agents being used to combat this disease. However, MM cells still develop resistance to proteasome inhibitors such as carfilzomib. Toward this end, we have established carfilzomib-resistant derivatives of MM cell lines. We found that resistance to carfilzomib was associated with elevated levels of prosurvival autophagy, and Kruppel-like factor 4 (KLF4) was identified as a contributing factor. Expression levels as well as nuclear localization of KLF4 protein were elevated in MM cells with acquired carfilzomib resistance. Chromatin immunoprecipitations indicated that endogenous KLF4 bound to the promoter regions of the SQSTM1 gene encoding the ubiquitin-binding adaptor protein sequestosome/p62 that links the proteasomal and autophagic protein degradation pathways. Ectopic expression of KLF4 induced upregulation of SQSTM1. On the other hand, inhibitors of autophagy sensitized MM cells to carfilzomib, even in carfilzomib-resistant derivatives having increased expression of the multidrug resistance protein P-glycoprotein. Thus, we report here a novel function for KLF4, one of the Yamanaka reprogramming factors, as being a contributor to autophagy gene expression which moderates preclinical proteasome inhibitor efficacy in MM.

Related Materials

Product #

Image

Description

Molecular Formula

Add to Cart

SAB2701263
Anti-DCTN4 antibody produced in rabbit, affinity isolated antibody, buffered aqueous solution
SAB2107220
Anti-DCTN4 antibody produced in rabbit, affinity isolated antibody
SAB2105017
Anti-DCTN4, (N-terminal) antibody produced in rabbit, affinity isolated antibody
GW22005A Anti-GTF2H1 (ab1) antibody produced in chicken, affinity isolated antibody, buffered aqueous solution
GW22005B Anti-GTF2H1 (ab2) antibody produced in chicken, affinity isolated antibody, buffered aqueous solution
AV100811
Anti-GTF2H1 antibody produced in rabbit, IgG fraction of antiserum
SAB2104463
Anti-GTF2H1 antibody produced in rabbit, affinity isolated antibody
AV38430
Anti-KLF4 antibody produced in rabbit, affinity isolated antibody, lyophilized powder
AV35721
Anti-KLF4 antibody produced in rabbit, IgG fraction of antiserum
HPA002926
Anti-KLF4 antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution
SAB1300678
Anti-KLF4 antibody produced in rabbit, saturated ammonium sulfate (SAS) precipitated, buffered aqueous solution
SAB2105308
Anti-KLF4 antibody produced in rabbit, affinity isolated antibody
SAB2701975
Anti-KLF4 antibody produced in rabbit
SAB2106435
Anti-KLF4 antibody produced in rabbit, affinity isolated antibody
SAB4200361
Anti-LC3B antibody, Mouse monoclonal, clone LC3B-6, purified from hybridoma cell culture
SAB2700738
Anti-Map1lc3b antibody produced in rabbit, affinity isolated antibody, buffered aqueous solution
SAB3501065
Anti-MAP1LC3B antibody produced in rabbit, affinity isolated antibody
GW22431A Anti-NUP62 antibody produced in chicken, affinity isolated antibody, buffered aqueous solution
HPA005435
Anti-NUP62 antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution
SAB2101664
Anti-NUP62 antibody produced in rabbit, affinity isolated antibody
SAB1410438
Anti-NUP62 antibody produced in rabbit, purified immunoglobulin, buffered aqueous solution
WH0002965M1
Monoclonal Anti-GTF2H1 antibody produced in mouse, clone 1F12-1B5, purified immunoglobulin, buffered aqueous solution
SAB1403894
Monoclonal Anti-GTF2H1, (C-terminal) antibody produced in mouse, clone 4B9, purified immunoglobulin, buffered aqueous solution
SAB5300069
Monoclonal Anti-KLF4 antibody produced in mouse, clone 1E6, ascites fluid
WH0081631M1
Monoclonal Anti-MAP1LC3B antibody produced in mouse, clone 4E11, purified immunoglobulin, buffered aqueous solution
SAB1405293
Monoclonal Anti-MAP1LC3B antibody produced in mouse, clone 4G7, purified immunoglobulin, buffered aqueous solution
WH0023636M2
Monoclonal Anti-NUP62 antibody produced in mouse, clone 2D3, purified immunoglobulin, buffered aqueous solution
SAB1404985
Monoclonal Anti-NUP62 antibody produced in mouse, clone 1F12, purified immunoglobulin, buffered aqueous solution