ABC Transporters in Cancer Stem Cells: Beyond Chemoresistance

Abstract

The efficacy of chemotherapy is one of the main challenges in cancer treatment and one of the major obstacles to overcome in achieving lasting remission and a definitive cure in patients with cancer is the emergence of cancer resistance. Indeed, drug resistance is ultimately accountable for poor treatment outcomes and tumour relapse. There are various molecular mechanisms involved in multidrug resistance, such as the change in the activity of membrane transporters primarily belonging to the ATP binding cassette (ABC) transporter family. In addition, it has been proposed that this common feature could be attributed to a subpopulation of slow-cycling cancer stem cells (CSCs), endowed with enhanced tumorigenic potential and multidrug resistance. CSCs are characterized by the overexpression of specific surface markers that vary in different cancer cell types. Overexpression of ABC transporters has been reported in several cancers and more predominantly in CSCs. While the major focus on the role played by ABC transporters in cancer is polarized by their involvement in chemoresistance, emerging evidence supports a more active role of these proteins, in which they release specific bioactive molecules in the extracellular milieu. This review will outline our current understanding of the role played by ABC transporters in CSCs, how their expression is regulated and how they support the malignant metabolic phenotype. To summarize, we suggest that the increased expression of ABC transporters in CSCs may have precise functional roles and provide the opportunity to target, particularly these cells, by using specific ABC transporter inhibitors.

HDAC2 and PCNA expression is correlated to decreasing of endoxifen sensitivity in human breast cancer stem cells ALDH+

“…13 One mechanism of drug resistance is overexpression of efflux transporters such as ATP binding casette subfamily B member 1/ABCB1 (P-glycoprotein), where its expression is also found high in breast cancer stem cells. 14 Proliferating cell nuclear antigen (PCNA) is a cofactor of DNA polymerases that coordinate several functions in the replication process. Some studies reported that HDAC1 interacts with PCNA and HDAC1 and 2 are associated with newly replicated DNA.…”

“…Penelitian kami sebelumnya menggunakan jaringan kanker payudara mengungkapkan bahwa ekspresi gen histone deacetylase 2 (HDAC2) dan proliferating cell nuclear antigen (PCNA) ditemukan perbedaan signifikan setelah terapi neoajuvan hormon dan kemoterapi. Penelitian ini bertujuan untuk menganalisis hubungan antara ekspresi HDAC2 dan PCNA dengan kelangsungan hidup sel punca kanker payudara dengan penanda aldehyde dehydrogenase + (ALDH+) yang diberi perlakuan endoksifen.Metode: Sampel adalah BCSC primer manusia ALDH+ yang diberi perlakuan endoksifen 4 uM masingmasing selama 2,4,6,8,10,12,14 hari. Viabilitas sel dilihat dengan menggunakan trypan blue dan ekspresi mRNA HDAC2 dan PCNA ditentukan menggunakan qRT-PCR.Hasil: Viabilitas BCSCs ALDH + menurun setelah 2 sampai 4 hari pemberian endoksifen.…”

“…Metode: Sampel adalah BCSC primer manusia ALDH+ yang diberi perlakuan endoksifen 4 uM masingmasing selama 2,4,6,8,10,12,14 hari. Viabilitas sel dilihat dengan menggunakan trypan blue dan ekspresi mRNA HDAC2 dan PCNA ditentukan menggunakan qRT-PCR.…”

The Interactions Between Cancer Stem Cells and the Innate Interferon Signaling Pathway

“…CSCs are invulnerable to conventional anticancer therapies, as they have an intrinsic chemo-and radio-resistant profile that enables their survival and clonal expansion over those cells unable to resist therapeutic pressures. Expression of drug efflux pumps, such as ABCG2 and MDR1, not only allows CSCs to evade the lethal impact of chemotherapy (140), but these pumps also seem to promote stem-like capacities via facilitating the clearance of endogenous anti-tumorigenic molecules from the cell while redirecting pro-tumorigenic molecules to the cell's surface receptors (141). Other common mechanisms of chemoresistance are ALDH activity, expression of pro-survival BCL-2 protein family members and activation of several signaling pathways involved in chemo-and radio-resistance, including MYC and AKT1 (142).…”

Novel mTORC1 inhibitors kill Glioblastoma stem cells

“…Glioblastoma multiforme (GBM) is a deadly tumor with a usual post-diagnosis survival of 15 months. One major hypothesis for GBM tumor resistance is that GBM stem cells (GBMSCs) resist standard chemotherapy and through growth, proliferation, and mutation cause tumor relapse (1,2). Several studies have shown that mTORC1 inhibition through rapamycin attenuates cancer stem cell chemotherapy insensitivity (3)(4)(5).…”