A Role for OCT4 in Tumor Initiation of Drug-Resistant Prostate Cancer Cells

Abstract

Drug resistance remains a clinical challenge in cancer treatment due to poor understanding of underlying mechanisms. We have established several drug-resistant prostate cancer cell lines by long-term culture in medium containing chemotherapeutic drugs. These resistant lines displayed a significant increase in side population cells due to overexpression of drug efflux pumps including ABCG2/BCRP and MDR1/Pgp. To uncover potential mechanisms underlying drug resistance, we performed microarray analysis to identify differentially expressed genes in 2 drug-resistant lines. We observed that POU5F1/OCT4, a transcription factor key to regulating pluripotency in embryonic stem cells, was upregulated in drug-resistant lines and accompanied by transcriptional activation of a set of its known target genes. Upregulation of OCT4 in drug-resistant cells was validated by RT-PCR and sequencing of PCR products as well as confirmation by Western blot and specific shRNA knockdown. Analysis of the regulatory region of POU5F1/OCT4 revealed a reduction of methylation in drug-resistant cell lines. Furthermore, these drug-resistant cells exhibited a significant increase in tumorigenicity in vivo. Subcutaneous inoculation of as few as 10 drug-resistant cells could initiate tumor formation in SCID mice, whereas no detectable tumors were observed from the parental line under similar conditions, suggesting that these drug-resistant cells may be enriched for tumor-initiating cells. Knocking down OCT4 expression by specific shRNAs attenuated growth of drug-resistant cells. Our data suggest that OCT4 re-expression in cancer cells may play an important role in carcinogenesis and provide one possible mechanism by which cancer cells acquire/maintain a drug-resistant phenotype.

Increased Chemosensitivity via Targeting Testicular Nuclear Receptor 4 (TR4)-Oct4-Interleukin 1 Receptor Antagonist (IL1Ra) Axis in Prostate Cancer CD133+ Stem/Progenitor Cells to Battle Prostate Cancer

“…We found that TR4 may exert its action through Oct4-IL1Ra signaling. The role of Oct4 in drug-resistant PCa cells has been reported (18), and TR4 regulation of Oct4 has also been suggested (36). Our results showed TR4 modulation of Oct4 in PCa stem/progenitor cells and revealed its downstream molecule, IL1Ra.…”

“…Linn et al (18) reported that drug-resistant PCa cells express high levels of Oct4, and knockdown of this molecule attenuated growth of the drug-resistant cells. Significant upregulation of Oct4 was also observed in cisplatin-resistant patients with oral squamous cell carcinomas (34).…”

“…3, mRNA level (a) and protein level (b)). We used TR4 knockdown PCa stem/progenitor and scrambled control cells and examined mRNA expressions of Oct4 and several Oct4 downstream genes associated with drug resistance and stem cells (18,33,37), including GATA6, GDF6, KLF5, and IL1RN, and found that IL1RN gene expression was most significantly reduced in the TR4 knockdown PCSCs (Fig. 3c, left, mRNA level; right, protein level) and C4-2/CD133 ϩ stem/progenitor cells (Fig.…”

“…Increasing evidence has indicated that PCa stem/progenitor cells, which are characterized with high expression of CD133, CD44, and Oct4 (17,18), are resistant to chemotherapeutic drugs (19,20), and early reports suggested that chemoresistance in cancer stem cells could be due to their high expression of drug-resistant related genes, including ABCB1/MDR1, ABCG2/BCRP, and ABCC1/MRP1 (21,22).…”

The impact of melatonin and carbon ion irradiation on cancer stem cells

“…Ponti and colleagues observed that a breast cancer cell line that developed into spheroids also had CD44+/CD24low/-phenotype and expressed the transcription factor OCT4 [91]. The expression of OCT4 has an essential role in carcinogenesis and offers a probable mechanism by which cancer cells obtain or sustain the therapy resistance phenotype [92,93]. Moreover, overexpression of this gene was related to metastasis and poor prognosis in various types of cancer, including colorectal, lung and gliomas [94][95][96][97][98][99].…”