Article

MiR-96 downregulates REV1 and RAD51 to promote cellular sensitivity to cisplatin and PARP inhibition.

Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
Cancer Research (Impact Factor: 9.28). 07/2012; 72(16):4037-46. DOI: 10.1158/0008-5472.CAN-12-0103
Source: PubMed

ABSTRACT Cell survival after DNA damage relies on DNA repair, the abrogation of which causes genomic instability. The DNA repair protein RAD51 and the trans-lesion synthesis DNA polymerase REV1 are required for resistance to DNA interstrand cross-linking agents such as cisplatin. In this study, we show that overexpression of miR-96 in human cancer cells reduces the levels of RAD51 and REV1 and impacts the cellular response to agents that cause DNA damage. MiR-96 directly targeted the coding region of RAD51 and the 3'-untranslated region of REV1. Overexpression of miR-96 decreased the efficiency of homologous recombination and enhanced sensitivity to the PARP inhibitor AZD2281 in vitro and to cisplatin both in vitro and in vivo. Taken together, our findings indicate that miR-96 regulates DNA repair and chemosensitivity by repressing RAD51 and REV1. As a therapeutic candidate, miR-96 may improve chemotherapeutic efficacy by increasing the sensitivity of cancer cells to DNA damage.

1 Follower
 · 
157 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: 5-FU is an anticancer drug that is widely used to treat cancers, including colorectal cancer (CRC); however, chemoresistance to 5-FU remains an important problem to be resolved. The role of microRNAs (miRs) in chemosensitivity has recently been studied in the development of therapeutic strategies to overcome drug resistance. Here, we focused on miR-96, which has been reported to demonstrate chemosensitivity. We investigated whether 5-FU sensitivity may be modulated by miR-96 in monolayer cells and whether this relationship also applies for drug resistance in 3D tumor spheroids (TSs). When the level of miR-96 increased, the expression of the anti-apoptotic regulator XIAP and p53 stability regulator UBE2N decreased, resulting in increased apoptosis and growth inhibition following 5-FU exposure. Transfection of miR-96 inhibitors resulted in an overexpression of XIAP and UBE2N, yet only minimal change was induced in apoptosis. Nonetheless, luciferase assay failed to show direct interactions between miR-96 and these genes. In TSs, 5-FU resistance corresponded to a significantly lower level of miR-96, however only XIAP, not UBE2N, was up-regulated demonstrating partial agreement with the 2D condition regarding target expression. Overall, these results suggest that miR-96 may modulate 5-FU sensitivity in CRC cells by promoting apoptosis; however, differential expression of target genes in TSs warrants further studies on the 5-FU resistance mechanism under 3D conditions.
    Archives of Pharmacal Research 12/2014; 38(2). DOI:10.1007/s12272-014-0528-9 · 1.75 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: We have examined the mechanisms of therapy resistance mediated by cancer genome stabilization.•We assess the targeting of RAD51 to overcome resistance, defining it as an effective therapy for cancer treatment.•There are direct and indirect methods to inhibit RAD51 activity via six different therapeutic mechanisms.•We evaluate the current clinical applications for targeting RAD51 in ovarian, colorectal and malignant gliomas.•RAD51 represents a new clinical target to sensitize tumours to standard therapeutic regimens that induce DNA damage.
    Cancer Treatment Reviews 11/2014; 41(1). DOI:10.1016/j.ctrv.2014.10.006 · 6.47 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: REV3L, the catalytic subunit of DNA Polymerase ζ (Polζ), plays a significant role in the DNA damage tolerance mechanism of translesion synthesis (TLS). The role of REV3L in chemosensitivity of cervical cancer needs exploration. In the present study, we evaluated the expression of the Polζ protein in paraffin-embedded tissues using immunohistochemistry and found that the expression of Polζ in cervical cancer tissues was higher than that in normal tissues. We then established some cervical cancer cell lines with REV3L suppression or overexpression. Depletion of REV3L suppresses cell proliferation and colony formation of cervical cancer cells through G1 arrest, and REV3L promotes cell proliferation and colony formation of cervical cancer cells by promoting G1 phase to S phase transition. The suppression of REV3L expression enhanced the sensitivity of cervical cancer cells to cisplatin, and the overexpression of REV3L conferred resistance to cisplatin as evidenced by the alteration of apoptosis rates, and significantly expression level changes of anti-apoptotic proteins B-cell lymphoma 2 (Bcl-2), myeloid cell leukemia sequence 1 (Mcl-1) and B-cell lymphoma-extra large (Bcl-xl) and proapoptotic Bcl-2-associated x protein (Bax). Our data suggest that REV3L plays an important role in regulating cervical cancer cellular response to cisplatin, and thus targeting REV3L may be a promising way to alter chemosensitivity in cervical cancer patients.
    PLoS ONE 10(3):e0120334. DOI:10.1371/journal.pone.0120334 · 3.53 Impact Factor

Full-text (2 Sources)

Download
18 Downloads
Available from
Jul 18, 2014