Cystathionine β‐synthase regulates mitochondrial morphogenesis in ovarian cancer

Abstract

Deregulation of mitochondrial morphogenesis, a dynamic equilibrium between mitochondrial fusion and fission processes, is now evolving as a key metabolic event that fuels tumor growth and therapy resistance. However, fundamental knowledge underpinning how cancer cells reprogram mitochondrial morphogenesis remains incomplete. Here, we report that cystathionine β-synthase (CBS) reprograms mitochondrial morphogenesis in ovarian cancer (OvCa) cells by selectively regulating the stability of mitofusin 2 (MFN2). Clinically, high expression of both CBS and MFN2 implicates poor overall survival of OvCa patients, and a significant association between CBS and MFN2 expression exists in individual patients in the same data set. The silencing of CBS by small interfering RNA or inhibition of its catalytic activity by a small molecule inhibitor creates oxidative stress that activates JNK. Activated JNK phosphorylates MFN2 to recruit homologous to the E6-AP carboxyl terminus' domain-containing ubiquitin E3 ligase for its degradation via the ubiquitin-proteasome system. Supplementation with hydrogen sulfide or glutathione (the catalytic products of CBS enzymatic activity), anti-oxidants, or a JNK inhibitor restores MFN2 expression. In CBS-silenced orthotopic xenograft tumor tissues, MFN2 but not MFN1 is selectively downregulated. In summary, this report reveals a role for deregulated mitochondrial morphogenesis in OvCa, suggests one of the mechanisms for this deregulation, and provides a way to correct it through modulation of the metabolic enzyme CBS.-Chakraborty, P. K., Murphy, B., Mustafi, S. B., Dey, A., Xiong, X., Rao, G., Naz, S., Zhang, M., Yang, D., Dhanasekaran, D. N., Bhattacharya, R., Mukherjee, P. Cystathionine β-synthase regulates mitochondrial morphogenesis in ovarian cancer.

Mitochondrial Dynamics: Fission and Fusion in Fate Determination of Mesenchymal Stem Cells

“…Similarly, treatment with the MEK inhibitor, PD325901, results in dramatic decline in both ERK and Drp1616 phosphorylation, effectively reversing mitochondrial fragmented phenotype in oncogenic Ras-induced embryonic kidney cells (Kashatus et al, 2015). JNK activation is connected to Mfn2 but not Mfn1 turnover (Chakraborty et al, 2018). Leboucher et al demonstrated FIGURE 1 | Phosphorylated Drp1-mediated mitochondrial fission.…”

“…JNK activation is connected to Mfn2 but not Mfn1 turnover ( Chakraborty et al, 2018 ). Leboucher et al demonstrated that JNK mediated the phosphorylation of Mfn2 at Ser27 of sarcoma U2OS cells in response to cellular stress, which contributed to ubiquitin-proteasome degradation in Mfn2 and enhanced apoptosis ( Leboucher et al, 2012 ).…”

Dysregulated Mitochondrial Dynamics and Metabolism in Obesity, Diabetes, and Cancer

“…It is worth noting that the higher expression of Mfn2 has also been reported in lung adenocarcinoma tissues as compared to adjacent normal tissues, and Mfn2 knockdown results in impaired cancer cell proliferation (81). In ovarian cancer (82), breast cancer (83), and melanoma (84), Mfn2 knockdown suppresses oxygen consumption rate (OCR). In pancreatic cancer cells (PANC-1), Mfn2 knockdown enhances mitochondria-dependent energy metabolism by promoting activity of electron transport chain complexes (85).…”

Targeting Glutathione and Cystathionine β-Synthase in Ovarian Cancer Treatment by Selenium–Chrysin Polyurea Dendrimer Nanoformulation

“…Additionally, we previously reported cysteine concentration (total and protein bound) in peripheral blood as a promising marker for screening, early diagnosis, outcome, and follow-up of ovarian cancer [25]. The overexpression of CBS associated with H 2 S generation was reported in several ovarian cancer cell lines and tumor models and was proposed to contribute to mitochondrial morphogenesis reprogramming [26], energy metabolism regulation [27], and deregulation of lipid metabolism [26], thereby promoting tumor growth and chemoresistance [12]. Indeed, CBS inhibition may afford anti-tumor activity and abrogation of chemoresistance via attenuated GSH synthesis and nuclear metallothionein expression [12,28].…”