Nuclear expression of dynamin-related protein 1 in lung adenocarcinomas

Abstract

Dynamin-related protein 1 (DRP1), an 80 kDa GTPase, is involved in mitochondrial fission and anticancer drugmediated cytotoxicity, which implicate an association with disease progression of cancer. In this study we investigated the prognostic value of DRP1 in lung adenocarcinomas. Using immunohistochemistry, we measured the expression of DRP1 in 227 patients with lung adenocarcinomas. Expression of DRP1 was confirmed by immunoblotting. The correlation between DRP1 expression and clinicopathological parameters was analyzed by statistical analysis. Difference of survivals between different groups was compared by a logrank test. The results showed that DRP1 expression was detected in 202 patients with lung adenocarcinomas. Among these, nuclear DRP1 (DRP1 nuc ) was detected in 184 patients. A significant difference was found in cumulative survival between patients with high DRP1 nuc levels and those with DRP1 cyt levels (Po0.001). In vitro, hypoxia increased DRP1 nuc levels and cisplatin resistance. Antibodies specific to DRP1 co-precipitated a human homologue of yeast Rad23 protein A (hHR23A) and silencing of hHR23A decreased the nuclear DRP1 level and cisplatin resistance. In conclusion, DRP1 nuc is highly expressed in lung adenocarcinomas, and correlates with poor prognosis. Nuclear DRP1 may increase drug resistance during hypoxia, and hHR23A is essential for nuclear transportation of DRP1. Our results suggest that other than the protein level alone, intracellular distribution of the protein is critical for determining the protein function in cells.

Human papillomavirus infection and expression of ATPase family AAA domain containing 3A, a novel anti-autophagy factor, in uterine cervical cancer

“…By showing that hypoxia-induced autophagic vesicles were encircled by DRP1 and the human homolog of yeast Rad23 protein A (hHR23A) as well, our previous data suggest that DRP1 and hHR23A may play a role in mammalian cell autophagy (17), based on the fact that hFis1 required DRP1 to carry out fission activities (37). Moreover, our current results provide a reasonable interpretation for the involvement of ATAD3A in autophagy and apoptosis, because ATAD3A may be able to provide energy for the movement of transport vesicles, transporting phospholipids and proteins from the ER, and mitochondria-associated membranes to the mitochondria.…”

“…Immunohistochemical staining was performed on paraffin-embedded tissues by an immunoperoxidase method as previously described (6,(14)(15)(16)(17)(18). Following removal of paraffin with xylene and alcohol, pathological sections were incubated with antibodies specific to ATAD3A (18), hepatocyte growth factor (HGF), HGF receptor (HGFR, or product of proto-oncogene c-met, c-MET), IL-8 (R&D Systems, Minneapolis, MN) or Ki-67 (zymed, San Francisco, CA).…”

“…The non-tumor counterpart of the cervical tissue served as a negative control, and a section of mouse liver tissue was used as positive control for each run of immunohistochemical staining. The same antibodies were used for immunoblotting, which was performed as previously (14)(15)(16)(17)(18).…”

The mitochondrial dynamics in cancer and immune-surveillance

“…By contrast, hypoxic in vitro studies performed in other cell lines from the same tumor highlighted how hypoxic TME can lead to Mfn-1-dependent mitochondria elongation, with consequent increased organelle respiratory capacity and also increased resistance to apoptosis [55]. The resistance to apoptosis upon cisplatin treatment has been associated with i) lung adenocarcinoma patients with an unusual sequestration of Drp1 inside the nucleus (no more available to promote OMM hemifission) [56], ii) in tongue squamous cell carcinoma (TSCC) with the inhibition of Mff protein translation and mitochondria fission [57], and iii) apoptosis-resistant neuroblastoma cells with increased Opa-1 levels and fused mitochondria [58]. Further, deletion of the miR494-containing chromosomal fragment frequently occurs in different cancers [59] and, interestingly, restoring miR494 levels in renal carcinoma cells promotes cellular apoptosis in a process requiring Drp1-dependent mitochondrial fragmentation [60,61].…”

Expression of xeroderma pigmentosum complementation group C protein predicts cisplatin resistance in lung adenocarcinoma patients

“…The synergistic action of XPC and hHR23B results in cytoresistance to chemotherapeutics and irradiation (23). Our recent report also showed that increase in the amount of nuclear dynamin-related protein 1 (DRP1) accompanied by nuclear accumulation of hHR23A was imperative for the increase of cisplatin resistance (25). Both hHR23A and hHR23B are involved in DNA repair and p53 stabilization.…”