MICU1 drives glycolysis and chemoresistance in ovarian cancer

Abstract

Cancer cells actively promote aerobic glycolysis to sustain their metabolic requirements through mechanisms not always clear. Here, we demonstrate that the gatekeeper of mitochondrial Ca2+ uptake, Mitochondrial Calcium Uptake 1 (MICU1/CBARA1) drives aerobic glycolysis in ovarian cancer. We show that MICU1 is overexpressed in a panel of ovarian cancer cell lines and that MICU1 overexpression correlates with poor overall survival (OS). Silencing MICU1 in vitro increases oxygen consumption, decreases lactate production, inhibits clonal growth, migration and invasion of ovarian cancer cells, whereas silencing in vivo inhibits tumour growth, increases cisplatin efficacy and OS. Mechanistically, silencing MICU1 activates pyruvate dehydrogenase (PDH) by stimulating the PDPhosphatase-phosphoPDH-PDH axis. Forced-expression of MICU1 in normal cells phenocopies the metabolic aberrations of malignant cells. Consistent with the in vitro and in vivo findings we observe a significant correlation between MICU1 and pPDH (inactive form of PDH) expression with poor prognosis. Thus, MICU1 could serve as an important therapeutic target to normalize metabolic aberrations responsible for poor prognosis in ovarian cancer.

Therapeutic Inhibition of the Receptor Tyrosine Kinase AXL Improves Sensitivity to Platinum and Taxane in Ovarian Cancer

“…Despite effectiveness of the first-line carboplatin and paclitaxel regimen, the majority of ovarian cancer patients die because they develop chemoresistant disease (36,37). Numerous receptors and pathways are known to be critical in ovarian cancer chemoresistance (38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51), but no targeted agent has been shown to enhance sensitivity to both carboplatin and paclitaxel. Here, we present several lines of evidence that AXL has a critical role in resistance to paclitaxel and carboplatin.…”

Akt‐mediated phosphorylation of MICU 1 regulates mitochondrial Ca 2+ levels and tumor growth

“…Moreover, MICU1 appears to be a favorable prognostic marker in renal cancer (https://www.proteinatlas.org/ENSG00000107745-MICU1/pathology). In contrast, high MICU1 levels confer chemoresistance to ovarian cancer cells (Chakraborty et al , ), and MICU1 downregulation has been associated with a higher sensitivity to apoptotic stress and impaired endothelial cell migration (Mallilankaraman et al , ). However, an accelerated proliferation of MICU1 ‐knockdown hepatocytes has been recently observed following treatment with NIM811 (Antony et al , ), which is an inhibitor of the mitochondrial permeability transition pore (mPTP), the channel responsible for the initiation of mitochondrial cell death programs (Bonora et al , ).…”

Calcium homeostasis in cisplatin resistant epithelial ovarian cancer

“…Drugs such as arsenic trioxide (As 2 O 3 ) (Gunes et al 2009) and gamitrinib (Park et al 2014) were suggested to promote ER Ca 2+ release during short-term exposure. Short-term exposure of cancer cells to cisplatin (Shen et al 2016;Chakraborty et al 2017), doxorubicin (Giorgi et al 2015a), or photodynamic therapy (PDT) (Giorgi et al 2015b), may enhance ER-mitochondria Ca 2+ transfer in some models. Examples of the remodeling of Ca 2+ signaling with longer term drug treatments include altered store-operated Ca 2+ entry (SOCE) as a result of treatment with 5-Fluorouracil (Kondratska et al 2014;Tang et al 2017), gemcitabine (Kondratska et al 2014) or cisplatin (Schmidt et al 2014).…”