Parkin regulates paclitaxel sensitivity in breast cancer via a microtubule‐dependent mechanism

Abstract

Parkin is an E3 ubiquitin ligase encoded by the Parkin gene (also called PARK2, located at 6q25.2-q27) and is involved in the pathogenesis of Parkinson's disease and the development of cancer. Recently, Parkin has been demonstrated to interact with the microtubule cytoskeleton. However, the biological implication of the Parkin-microtubule axis has been poorly explored. In this study, we report for the first time that Parkin modulates sensitivity of the chemotherapeutic agent paclitaxel in breast cancer, via a microtubule-dependent mechanism. Our data reveal that Parkin binds to the outer surface of microtubules and increases paclitaxel-microtubule interaction, resulting in enhanced paclitaxel-induced microtubule assembly and stabilization. Our data further show that Parkin promotes the activity of paclitaxel to trigger multinucleation and apoptosis, rendering breast cancer cells more sensitive to this drug. Moreover, Parkin expression correlates with the pathological response of tumours to preoperative paclitaxel-containing chemotherapy. In addition, expression of Parkin also correlates with the sensitivity of paclitaxel in primary cultures of breast cancer cells. Our results identify Parkin as a novel mediator of paclitaxel sensitivity in breast cancer. In addition, our study suggests that patients harbouring tumours with high Parkin level would be more likely to benefit from paclitaxel-containing regimens.

Inactivation of parkin by promoter methylation correlated with lymph node metastasis and genomic instability in nasopharyngeal carcinoma

“…Wang et al 33 demonstrated that parkin promoted the activity of paclitaxel to trigger multinucleation and apoptosis, rendering breast cancer cells more sensitive to this drug. Another study reported that a p53 fusion protein TAT-ODD-p53 had a significant and preferential radiosensitizing effect on hypoxic breast cancer cells by inhibiting parkin-mediated mitophagy.…”

“…33 Briefly, human tissue sections were stained for the expression of parkin (1:100; Abcam, UK) and detected by streptavidin-biotin-horseradish peroxidase complex formation. Tumor sections that were stained by isotype-matched immunoglobulin G instead of primary antibodies were used as a negative control.…”

Parkin induces G2/M cell cycle arrest in TNF-α-treated HeLa cells

“…Many reports have suggested that parkin overexpression results in inhibition of cancer cell growth [4e6]. In the breast cancer cell line MCF7, parkin stabilizes microtubules, increases sensitivity to anti-cancer agents, and induces growth arrest [10]. There is evidence that parkin can also affect energy metabolism, namely the Warburg effect, leading to suppression of tumorigenesis in lung cancer and colon cancer cells [11].…”

Parkin induces apoptotic cell death in TNF-α-treated cervical cancer cells

“…These studies attracted interest in studying the mechanisms by which parkin acts as a tumor suppressor. In breast cancer, parkin stabilizes microtubules and increases susceptibility to anti-cancer agents (13). In the breast cancer cell line MCF7, parkin reduces cell growth by inducing expression of cyclin-dependent kinase 6 (CDK6) (8).…”