Increased mitochondrial fission promotes autophagy and hepatocellular carcinoma cell survival through the ROS-modulated coordinated regulation of the NFKB and TP53 pathways

Abstract

Mitochondrial morphology is dynamically remodeled by fusion and fission in cells, and dysregulation of this process is closely implicated in tumorigenesis. However, the mechanism by which mitochondrial dynamics influence cancer cell survival is considerably less clear, especially in hepatocellular carcinoma (HCC). In this study, we systematically investigated the alteration of mitochondrial dynamics and its functional role in the regulation of autophagy and HCC cell survival. Furthermore, the underlying molecular mechanisms and therapeutic application were explored in depth. Mitochondrial fission was frequently upregulated in HCC tissues mainly due to an elevated expression ratio of DNM1L to MFN1, which significantly contributed to poor prognosis of HCC patients. Increased mitochondrial fission by forced expression of DNM1L or knockdown of MFN1 promoted the survival of HCC cells both in vitro and in vivo mainly by facilitating autophagy and inhibiting mitochondria-dependent apoptosis. We further demonstrated that the survival-promoting role of increased mitochondrial fission was mediated via elevated ROS production and subsequent activation of AKT, which facilitated MDM2-mediated TP53 degradation, and NFKBIA- and IKK-mediated transcriptional activity of NFKB in HCC cells. Also, a crosstalk between TP53 and NFKB pathways was involved in the regulation of mitochondrial fission-mediated cell survival. Moreover, treatment with mitochondrial division inhibitor-1 significantly suppressed tumor growth in an in vivo xenograft nude mice model. Our findings demonstrate that increased mitochondrial fission plays a critical role in regulation of HCC cell survival, which provides a strong evidence for this process as drug target in HCC treatment.

Mitochondrial elongation-mediated glucose metabolism reprogramming is essential for tumour cell survival during energy stress

“…35 Our previous study has also showed that increased mitochondrial fission attenuated carbonyl cyanidem-Chlorophenylhydrazone-induced apoptosis in HCC cells. 36 Additionally, not statistically significant difference of cell apoptosis was observed between cells with expression of DRP1 S637A and related controls under fed condition and no carbonyl cyanidem-Chlorophenylhydrazone treatment, although the percentage of apoptosis in tumour cells with DRP1 S637A expression seemed to be a little less (data not shown). The superficial inconsistency between these findings might mainly be explained by different nutrition condition.…”

Mitochondrial dynamics and cancer

“…Zhan et al 52 and Huang et al 58 MAPK: mitogen-activated protein kinase; ERK: extracellular signal-regulated protein kinase; mRNA: messenger RNA. cancer cells that normally display fragmented mitochondria, DRP1 inhibition sensitized them to treatment 10,48 or induced cell death per se, 49 underscoring the importance of understanding whether the induction of mitochondrial fragmentation or inhibition of fusion will only be useful to target cancer cells with tubular mitochondria.…”

“…51 Reduced cancer cell growth and/or spontaneous apoptosis induced by DRP1 inhibition alone or in combination with chemotherapy have been observed both in vitro and in vivo in several cancer types, including breast, colon, lung, pancreatic, hepatocellular carcinoma, and melanoma. 49,[52][53][54][55][56][57][58] Moreover, alterations in the levels of proteins regulating mitochondrial dynamics have been suggested as potential biomarkers of malignancy or as a target for therapy in diverse tumor types ( Table 2). In this regard, inhibition of mitochondrial fragmentation by silencing of DRP1 has been associated with increased genomic instability 49 and reduced migration and invasion 59 in breast cancer cell lines which normally have a high level of fragmented mitochondria.…”

The mitochondrial dynamics in cancer and immune-surveillance

“…Whilst mitophagy impairment could be beneficial for the tumor onset, at later stages of tumor progression mitophagy could become protective for these cells, presumably protecting tumor cells from excessive mitochondrial damage, ROS accumulation and apoptosis. For example, Drp1-dependent mitophagy is an important pro-survival event in hepatocellular carcinoma (HCC), protecting cancer cells from apoptosis through p53 and NF-κB modulation [144]. Similarly, in K-Ras induced lung cancers, inhibition of mitophagy leads to strong reduction in cell proliferation [145].…”

“…Interestingly, the oncogenic MAPK/ERK pathway, which is a driver of cancer progression in different tumors, is able to upregulate Drp1 activity in different cancers [147,148] by phosphorylation on serine residue Ser616 [147]. In several human cancers, a poor survival rate is associated with an increased Drp1 level [54,67,70,71,144,149] or a decreased Mfn-2 [150,151] or Mfn-1 amounts [144,152], as also confirmed by the emerging Bioinformatics databases displaying the expression levels of different mitochondria-shaping proteins in human tumors (see The Human Atlas Project [153] and Table 1 for details).…”