Combined gemcitabine and CHK1 inhibitor treatment induces apoptosis resistance in cancer stem cell-like cells enriched with tumor spheroids from a non-small cell lung cancer cell line

doi:10.1007/s11684-013-0270-6

Front Med

2013, Vol. 7

Issue (4) : 462-476 https://doi.org/10.1007/s11684-013-0270-6

RESEARCH ARTICLE

Combined gemcitabine and CHK1 inhibitor treatment induces apoptosis resistance in cancer stem cell-like cells enriched with tumor spheroids from a non-small cell lung cancer cell line

Douglas D. Fang(

), Joan Cao, Jitesh P. Jani, Konstantinos Tsaparikos, Alessandra Blasina, Jill Kornmann, Maruja E. Lira, Jianying Wang, Zuzana Jirout, Justin Bingham, Zhou Zhu, Yin Gu, Gerrit Los, Zdenek Hostomsky, Todd VanArsdale

Oncology Research Unit, Pfizer, Inc., 10777 Science Center Drive, San Diego, CA 92121, USA

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Abstract

Evaluating the effects of novel drugs on appropriate tumor models has become crucial for developing more effective therapies that target highly tumorigenic and drug-resistant cancer stem cell (CSC) populations. In this study, we demonstrate that a subset of cancer cells with CSC properties may be enriched into tumor spheroids under stem cell conditions from a non-small cell lung cancer cell line. Treating these CSC-like cells with gemcitabine alone and a combination of gemcitabine and the novel CHK1 inhibitor PF-00477736 revealed that PF-00477736 enhances the anti-proliferative effect of gemcitabine against both the parental and the CSC-like cell populations. However, the CSC-like cells exhibited resistance to gemcitabine-induced apoptosis. Collectively, the spheroid-forming CSC-like cells may serve as a model system for understanding the mechanism underlying the drug resistance of CSCs and for guiding the development of better therapies that can inhibit tumor growth and eradicate CSCs.

Keywords drug resistance cancer stem cell checkpoint kinase 1 (CHK1) PF-00477736 lung cancer tumorigenicity

Corresponding Author(s): Fang Douglas D.,Email:douglasfang@yahoo.com

Issue Date: 05 December 2013

Cite this article:

Douglas D. Fang,Joan Cao,Jitesh P. Jani, et al. Combined gemcitabine and CHK1 inhibitor treatment induces apoptosis resistance in cancer stem cell-like cells enriched with tumor spheroids from a non-small cell lung cancer cell line[J]. Front Med, 2013, 7(4): 462-476.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-013-0270-6
https://academic.hep.com.cn/fmd/EN/Y2013/V7/I4/462

Fig.1 Isolation of CSC-like cells from NCI-H1299 under serum-free culture conditions.(A) Morphology of the monolayer culture of the original NCI-H1299 cells (left panel), non-adherent 3D CSC-like cells (middle panel), and monolayer culture of cells differentiated from CSC-like cells (right panel). (B) Flow cytometric analyses of cell proliferation of the aforementioned cell types using a BrdU assay.

Fig.2 Differentiation and tumorigenesis of CSC-like cells. (A) Detection of expression of the epithelial lineage marker cytokeratin using flow cytometry. A PE-conjugated mouse isotype-matched antibodies (mIgG-PE) were used as the control (top panel). The data shown represent the results of three independent experiments. (B) limiting dilution assays. Solid line, CSC-like cells; dot line, parental cells. Significant differences in tumor volume were observed between the two groups (** <0.01, *** <0.001, ANOVA analysis)

Tab.1 Tumor incidence after 42 days post-implantation*

Fig.3 (A) spheroid reforming assay of CSC-like cells. CSC-like cells were disaggregated and seeded at various cell densities in stem cell medium in a 96-well cell culture plate, as indicated. Tumor spheroids (cellular aggregates with≥4 cells) were counted after 5 days. (B) The primary tumor cells isolated from CSC-like cell-derived xenografts reformed tumor spheroids under stem cell conditions. (C) The fold increase in the expression levels of representative genes in the -cultured spheroid CSC-like cells and in CSC-derived xenograft tumors compared with their counterparts (i.e., parental cells and parental cell-derived xenograft tumors), respectively.

Fig.4 Expression profile analysis of the cultured cells and derived xenografts. (A) Unsupervised hierarchical clustering dendrogram of genes differentially expressed in cultured CSC-like and parental cells, as well as their derived xenograft tumors, which are coded in colors. (B) Hierarchical clustering diagram of differentially expressed genes among cultured CSC-like cells, parental cells, and their derived xenograft tumors. A comparison of the overexpression of CD59 among cultured CSC-like cells, xenograft tumors, and cultured NCI-H1299 parental cells is shown. The list of genes is shown in Table 2. (C) Principal component analysis (PCA) of the genome-wide mRNA profiles. Each color-coded dot represents one sample in a 3D diagram showing their relative distribution. The data are summarized for the first three components, all of which account for 68% of the total variability. Results shown are from triplicates samples.

ID	Gene symbol	Change	ID	Gene symbol	Change
207347_at	ERCC6	up	226499_at	NRARP	up
212463_at	CD59	up	227529_s_at	AKAP12	up
219423_x_at	TNFRSF25	up	227530_at	AKAP12	up
1554452_a_at	HIG2	up	231067_s_at	—	up
1556773_at	—	up	211564_s_at	PDLIM4	up
206300_s_at	PTHLH	up	226863_at	FAM110C	up
219410_at	TMEM45A	up	201110_s_at	THBS1	up
218325_s_at	DIDO1	up	205534_at	PCDH7	up
228564_at	LOC375295	up	202179_at	BLMH	down
203372_s_at	SOCS2	up	202245_at	LSS	down
203373_at	SOCS2	up	210986_s_at	TPM1	down
201693_s_at	EGR1	up	210987_x_at	TPM1	down
205428_s_at	CALB2	up	211984_at	CALM1	down
1554008_at	OSMR	up	206117_at	TPM1	down
202949_s_at	FHL2	up	219985_at	HS3ST3A1	down
204017_at	KDELR3	up	218974_at	SOBP	down
219032_x_at	OPN3	up	206343_s_at	NRG1	down
220179_at	DPEP3	up	202931_x_at	BIN1	down
1568574_x_at	SPP1	up	210201_x_at	BIN1	down
213326_at	VAMP1	up	212437_at	CENPB	down
201844_s_at	RYBP	up	201628_s_at	RRAGA	down
201846_s_at	RYBP	up	206593_s_at	MED22	down
209380_s_at	ABCC5	up	219560_at	C22orf29	down
205691_at	SYNGR3	up	201929_s_at	PKP4	down
236915_at	—	up	48808_at	DHFR	down
227089_at	HBP1	up	1555427_s_at	SYNCRIP	down
206385_s_at	ANK3	up	200601_at	ACTN4	down
209442_x_at	ANK3	up	205471_s_at	DACH1	down
223631_s_at	C19orf33	up	227511_at	SAMD4B	down
214185_at	KHDRBS1	up	217992_s_at	EFHD2	down
223008_s_at	C9orf5	up	208939_at	SEPHS1	down
218686_s_at	RHBDF1	up	208940_at	SEPHS1	down
221567_at	NOL3	up	214930_at	SLITRK5	down
225918_at	LOC146346	up	238015_at	LOC201725	down
224743_at	IMPAD1	up	208784_s_at	KLHDC3	down
209278_s_at	TFPI2	up	37996_s_at	DMPK	down
224801_at	NDFIP2	up	211725_s_at	BID	down
201641_at	BST2	up	203664_s_at	POLR2D	down
1556166_x_at	—	up	209008_x_at	KRT8	down
232382_s_at	PCMTD1	up	202093_s_at	PAF1	down
207768_at	—	up	202264_s_at	TOMM40	down
209758_s_at	MFAP5	up	209675_s_at	HNRPUL1	down
221506_s_at	TNPO2	up	213429_at	BICC1	down
219884_at	LHX6	up	212131_at	LSM14A	down
213045_at	MAST3	up	215356_at	ECAT8	down
205742_at	TNNI3	up	212472_at	MICAL2	down
227948_at	FGD4	up	204589_at	NUAK1	down
235948_at	FAM80A	up	225471_s_at	AKT2	down
238168_at	TM4SF1	up	201480_s_at	SUPT5H	down
225257_at	CCDC97	down	213600_at	SIPA1L3	down
226156_at	AKT2	down	215429_s_at	ZNF428	down
205264_at	CD3EAP	down	203440_at	CDH2	down
202108_at	PEPD	down	229116_at	CNKSR2	down
204493_at	BID	down	227320_at	FAM101A	down
205740_s_at	RBM42	down	237034_at	—	down
219275_at	PDCD5	down	225688_s_at	PHLDB2	down
229587_at	SAE2	down	202626_s_at	LYN	down
227674_at	ZNF585A	down	238066_at	RBP7	down
202685_s_at	AXL	down	229139_at	JPH1	down
209583_s_at	CD200	down	224846_at	SHKBP1	down
206940_s_at	POU4F1	down	224694_at	ANTXR1	down
202625_at	LYN	down	201489_at	PPIF	down
230552_at	LOC284412	down	1569086_at	EML2	down
205347_s_at	TMSL8	down	222809_x_at	C14orf65	down
224209_s_at	GDA	down	216299_s_at	XRCC3	down
206170_at	ADRB2	down	221335_x_at	C19orf61	down
218625_at	NRN1	down	235019_at	CPM	down
220257_x_at	NXF2B	down	235706_at	CPM	down
220981_x_at	NXF2	down	243403_x_at	CPM	down
223188_at	C19orf61	down	219779_at	ZFHX4	down
228131_at	ERCC1	down	224507_s_at	MGC12916	down
208190_s_at	LSR	down	241733_at	C18orf54	down
240389_at	TRPM6	down	213053_at	KIAA0841	down
208713_at	HNRPUL1	down	225440_at	AGPAT3	down
218702_at	SARS2	down	227543_at	RNASEH2C	down
232079_s_at	PVRL2	down	225516_at	SLC7A2	down
234173_s_at	NXF2 /// NXF2B	down	228142_at	UCRC	down
219690_at	TMEM149	down	235236_at	—	down
225626_at	PAG1	down	220085_at	HELLS	down
213093_at	PRKCA	down	226279_at	PRSS23	down
206693_at	IL7	down	228489_at	TM4SF18	down
214046_at	FUT9	down	230061_at	TM4SF18	down

Tab.2 Comparison between the changes in gene expression profiles in cancer stem cell-like and in parental cells (≥3 fold)

Fig.5 Expression of stem cell markers CD44 and CD133 combined with EpCAM was determined using flow cytometry.

Fig.6 Comparison between the responses of the CSC-like cells and NCI-H1299 parental cells to drug treatments. (A) Resistance of the CSC-like cells to treatment using standard-of-care compounds. The results of cell viability assay are shown as percentage of viable cells (mean±SD) from triplicate experiments after normalizing with the controls. The IC in both cell types are indicated. (B) The inhibitory effect of gemcitabine alone and gemcitabine combined with the CHK1 inhibitor PF-00477736. The results of cell viability assay are shown as percentage inhibition (mean±SD; triplicates) after treatment with gemcitabine (Gem, 50 nM) alone or combined with PF-00477736 (540 nM). *<0.05, ** <0.01, one-way ANOVA. (C) Western blot analysis of CDK1, pCDK1, pCHK1, and cleaved PARP (clv) proteins in both cancer stem cell-like and parental cells treated with vehicle, gemcitabine, PF-00477736, and with gemcitabine combined with PF-00477736.

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