Drp1-mediated mitochondrial fission promotes cell proliferation through crosstalk of p53 and NF-κB pathways in hepatocellular carcinoma

Abstract

Mitochondria are highly dynamic and undergo constant fusion and fission that are essential for maintaining physiological functions of cells. Recently, we have reported that increased mitochondrial fission promotes autophagy and apoptosis resistance in hepatocellular carcinoma (HCC) cell through ROS-mediated coordinated regulation of NF-κB and p53 pathways. However, little is known about the roles of mitochondrial dynamics in HCC cell proliferation, another key feature of cancer cells. In this study, we systematically investigated the functional role of mitochondrial fission in the regulation of HCC cell proliferation. Furthermore, the underlying molecular mechanisms were deeply explored. We found that, increased mitochondrial fission by forced expression of Drp1 promoted the proliferation of HCC cells both in vitro and in vivo mainly by facilitating G1/S phase transition of cell cycle. Whereas, Drp1 knockdown or treatment with mitochondrial division inhibitor-1 induced significant G1 phase arrest in HCC cells and reduced tumor growth in the xenotransplantation model. We further demonstrated that the proliferation-promoting role of Drp1-mediated mitochondrial fission was mediated via p53/p21 and NF-κB/cyclins pathways. Moreover, the crosstalk between p53 and NF-κB pathways was proved to be involved in the regulation of mitochondrial fission-mediated cell proliferation. In conclusion, our findings demonstrate that Drp1-mediated mitochondrial fission plays a critical role in the regulation of cell cycle progression and HCC cell proliferation. Thus, targeting Drp1-dependent mitochondrial fission may provide a novel strategy for suppressing tumor growth of HCC.

MTFP1 overexpression promotes the growth of oral squamous cell carcinoma by inducing ROS production

“…In this study, we for the first time found that MTFP1, a novel regulator of mitochondrial fission, is frequently overexpressed in OSCC cells. Consistent with our results, overexpression of DRP1, another critical mitochondrial fission protein, has been observed in several other types of cancer, including liver (Zhan et al, ), colon (Inoue‐Yamauchi and Oda, ), and lung (Rehman et al, ) cancers. In addition, overexpression of MTFP1 also has been found in neuroblastoma and liver cancer (Applebaum et al, ; Zhang et al, ).…”

Mitochondrial dynamics as regulators of cancer biology

“…Given that DRP1 is upregulated in many cancers and is required for oncogenic transformation, indicates that cancer cells may be exquisitely sensitive to DRP1 inhibition. This hypothesis has thus far held true as pharmacological and genetic inhibition of DRP1 decreased the in vitro and in vivo growth of glioblastomas, melanoma, hepatocellular carcinoma, and mesothelioma [57,116,143,144]. …”

The mitochondrial dynamics in cancer and immune-surveillance

“…In addition, Drp1 has been shown to be implicated in the G1-S phase transition in hepatocellular carcinoma (HCC) cells, where increased Drp1 levels promote progression into cell cycle, through p53 inhibition (through ROS-dependent activation of the Akt/MDM2 pathway) and NK-κB activity promotion (which, in turn, induces expression of the specific cyclins D1 and E1) [66]. Further, lung cancer cells show an increased Drp1/Mfn-2 ratio, which promotes mitochondrial fission, whereas genetic manipulations restoring mitochondrial elongation reduce cancer cell proliferation and increase their sensitivity to apoptotic stimuli [67].…”