Role of GLI1 and NDRG1 in Increased Resistance to Apoptosis Induction.
We examined the effects of GLI1 expression in PW mouse embryo fibroblasts and H441 lung carcinoma cells. Ectopic expression of GLI1 in PW cells induced anchorage-independent growth and increased resistance to staurosporine-induced apoptosis, and overexpression of GLI1 in H441 cells caused resistance to apoptosis induced by staurosporine and etoposide. GLI1 expression in both H441 and PW cells was associated with increased expression of NDRG1, a gene known to be downregulated by the MYC family of proteins, indicating that upregulation of NDRG1 by GLI1 is not cell-type specific. Consistent with suppression of NDRG1 by c-MYC and N-MYC, increased NDRG1 expression correlated with decreased expression of c-MYC and N-MYC in GLI1-expressing H441 and GLI1-expressing PW cells, respectively. Downregulation of GLI1 expression in A549 cells by siRNA transfection increased sensitivity to etoposide-induced apoptosis, and downregulation of NDRG1 expression in H441 cells by siRNA transfection increased sensitivity to etoposide-induced apoptosis. Of clinical significance, inhibition of GLI1 and NDRG1 expression may increase sensitivity of cancer cells to chemotherapeutic drugs. Strategies that aim to inhibit GLI1 function and NDRG1 expression may be useful for targeted therapy of cancers induced by the SHH-GLI signaling pathway.
Department of Environmental Medicine, New York University School of Medicine, Tuxedo, New York.
Feng
F
Wu
Division of Pulmonary and Critical Care Medicine, and Department of Environmental Medicine, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.
William N
WN
Rom
Department of Environmental Medicine, New York University School of Medicine, Tuxedo, New York; Clinical Oncology, Merck & Co., Inc., Whitehouse Station, New Jersey.
Minori
M
Koshiji
Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, New York University School of Medicine, New York; Department of Environmental and Occupational Health Sciences, University of Louisville, Louisville, Kentucky.
Yiqun
Y
Mo
Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, New York University School of Medicine, New York; Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan.
Yukio
Y
Hosomi
Division of Pulmonary and Critical Care Medicine, and Department of Environmental Medicine, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.
Kam-Meng
KM
Tchou-Wong
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D005047:Etoposide / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D000071676:Zinc Finger Protein GLI1; D000099259:N-myc Downstream-Regulated Gene 1 Protein
D000972:Antineoplastic Agents, Phytogenic; D018797:Cell Cycle Proteins; D005047:Etoposide; D047908:Intracellular Signaling Peptides and Proteins; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D000099259:N-myc Downstream-Regulated Gene 1 Protein; C400551:GLI1 protein, human