DHRS2 inhibits cell growth and metastasis in ovarian cancer by downregulation of CHKα to disrupt choline metabolism

Abstract

The short-chain dehydrogenase/reductase (SDR) superfamily has essential roles in lipid metabolism and redox sensing. In recent years, accumulating evidence highlights the emerging association between SDR family enzymes and cancer. Dehydrogenase/reductase member 2(DHRS2) belongs to the NADH/NADPH-dependent SDR family, and extensively participates in the regulation of the proliferation, migration, and chemoresistance of cancer cells. However, the underlying mechanism has not been well defined. In the present study, we have demonstrated that DHRS2 inhibits the growth and metastasis of ovarian cancer (OC) cells in vitro and in vivo. Mechanistically, the combination of transcriptome and metabolome reveals an interruption of choline metabolism by DHRS2. DHRS2 post-transcriptionally downregulates choline kinase α (CHKα) to inhibit AKT signaling activation and reduce phosphorylcholine (PC)/glycerophosphorylcholine (GPC) ratio, impeding choline metabolism reprogramming in OC. These actions mainly account for the tumor-suppressive role of DHRS2 in OC. Overall, our findings establish the mechanistic connection among metabolic enzymes, metabolites, and the malignant phenotype of cancer cells. This could result in further development of novel pharmacological tools against OC by the induction of DHRS2 to disrupt the choline metabolic pathway.

Homomultivalent Polymeric Nanotraps Disturb Lipid Metabolism Homeostasis and Tune Pyroptosis in Cancer

“…Therefore, manipulating lipid metabolism has opened up a promising direction to achieve tumor treatments. A few strategies have been proposed to modulate the lipid metabolism in cancer, such as reprogramming the choline metabolism, [ 2 ] modulating the intracellular phosphatidylinositol levels in tumor cells, [ 3 ] or normalizing the lipid metabolism of conventional T cells to improve cancer immunotherapy, [ 4 ] while these strategies have limited efficiency and adverse effects toward normal tissues. Therefore, it is imperative to develop a new strategy that achieves lipid metabolism homeostasis interruption with high efficiency in targeting cells, while minimizing toxicity to normal cells.…”

Pharmacological effects of Niraparib and its combination with angiogenic inhibitor in ovarian cancer

“…Ovarian cancer (OC) represents the seventh most lethal female tumors worldwide [1][2][3][4][5]. The vast majority of OC patients exhibit recurrence and drug resistance within two years after surgery and platinum-containing chemotherapy [6].…”