title: Crosstalk between the mitochondrial fission protein, Drp1, and the cell cycle is identified across various cancer types and can impact survival of epithelial ovarian cancer patients.
abstract: Mitochondrial metabolic reprogramming is a hallmark of tumorigenesis. Although mitochondrial function can impact cell cycle regulation it has been an understudied area in cancer research. Our study highlights a specific involvement of mitochondria in cell cycle regulation across cancer types. The mitochondrial fission process, which is regulated at the core by Drp1, impacts various cellular functions. Drp1 has been implicated in various cancer types with no common mechanism reported. Our Drp1-directed large-scale analyses of the publically available cancer genomes reveal a robust correlation of Drp1 with cell-cycle genes in 29 of the 31 cancer types examined. Hypothesis driven investigation on epithelial ovarian cancer (EOC) revealed that Drp1 co-expresses specifically with the cell-cycle module responsible for mitotic transition. Repression of Drp1 in EOC cells can specifically attenuate mitotic transition, establishing a potential casual role of Drp1 in mitotic transition. Interestingly, Drp1-Cell-Cycle co-expression module is specifically detected in primary epithelial ovarian tumors that robustly responded to chemotherapy, suggesting that Drp1 driven mitosis may underlie chemo-sensitivity of the primary tumors. Analyses of matched primary and relapsed EOC samples revealed a Drp1-based-gene-expression-signature that could identify patients with poor survival probabilities from their primary tumors. Our results imply that around 60% of platinum-sensitive EOC patients undergoing relapse show poor survival, potentially due to further activation of a mitochondria driven cell-cycle regime in their recurrent disease. We speculate that this patient group could possibly benefit from mitochondria directed therapies that are being currently evaluated at various levels, thus enabling targeted or personalized therapy based cancer management.
authors: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors: Deepak Kumar
authors: DK
authors: Tanwar
authors: Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA.
authors: Danitra J
authors: DJ
authors: Parker
authors: Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA.
authors: Priyanka
authors: P
authors: Gupta
authors: Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA.
authors: Brian
authors: B
authors: Spurlock
authors: Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors: Ronald D
authors: RD
authors: Alvarez
authors: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
authors: Malay Kumar
authors: MK
authors: Basu
authors: Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA.
authors: Kasturi
authors: K
authors: Mitra
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D063646:Carcinogenesis; D002453:Cell Cycle / Q000235:genetics*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics*; D016000:Cluster Analysis; D034281:Dynamins; D004847:Epithelial Cells / Q000473:pathology / Q000502:physiology*; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D063154:Mitochondrial Dynamics; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D008938:Mitosis; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D017671:Platinum Compounds / Q000627:therapeutic use; D016019:Survival Analysis; D059467:Transcriptome
chemical_list: D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D017671:Platinum Compounds; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins
keywords: Drp1; cancer; cell cycle; genome analyses; mitochondria