Ms. Narjis Fatima has completed her Bachelors (BS/MSc.) in Biotechnology and currently enrolled in MS/Ph.D. program in Molecular Medicine at Molecular Oncology Lab, International Center for Chemical and Biological Sciences, University of Karachi.She is a meritorious student who secured highest CGP in her bachelors/ Masters (4 years) program in Biotechnology and was awarded Gold medal for standing first in the department. She was awarded a second gold medal for getting a first class first position in the entire Faculty of Science of the University of Karachi. She has always secured distinction or got positions in scientific workshops, Ph.D. credit hours course taught by distinguished international scientists and poster competitions. She is currently an MS/Ph.D. research fellow at ICCBS where she is working on Role of mitochondria in proliferation and survival of cancer cells. She has presented three posters related to her research at international conferences on Molecular medicine held in different cities of Pakistan and was appreciated by the jury. She has been awarded the meritorious Higher Education Commission scholarship for pursuing her MS research in Pakistan.
The High-Temperature Requirement A (HtrA) proteins are serine proteases that play a significant role in quality control of cellular proteins in a variety of organisms. They are mitochondrial chaperones, has the role in oncogenesis, neurodegenerative disorders, and apoptosis. Loss of HtrA function accumulates unfolded proteins, disrupts mitochondrial respiration, generates reactive oxygen species and leads to the proliferation of tumor cells while over expression of this family of proteases triggers cell death. Human HtrA proteases are of four types, HtrA1, HtrA2, HtrA3 and HtrA4. HtrA2/Omi resides in the mitochondrial intermembrane space (IMS), its paralogs HtrA1, 3 and 4 are most likely targeted to the secretory pathway.
HtrA2 promotes cell survival by the maintenance of mitochondrial homeostasis, however, under stressful conditions, they switch from a protector into a pro-apoptotic factor. HtrA1 and HtrA3 are involved in inhibition of TGF-b signaling and has the role as tumor suppressor in some cancers. Due to their potential interaction with caspase-mediated cell death pathways, HtrA serine protease pathway represents a potential target for therapeutic intervention.
In the current study, we have used colorectal cancer cell lines (HCT-116) and Prostate cancer cell lines (PC3) to analyze if this ATP depended on protease family (HtrA and other proteases of the interacting pathway) effects mitochondrial genome expression and its regulation in these cancers. Prostate cancer is the most common non-dermatologic cancer of males and is a leading cause of death in Pakistani males. Other most commonly diagnosed cancer in the country is colorectal cancer, which develops in the colon or the rectum and is the third leading cause of cancer death in both men and women. In Pakistan, multiple generations are affected with colorectal cancer at relatively young age, between 25 and 45 years. Two-third cases of colorectal cancers are sporadic, not genetic. Due to the high incidence of these cancers in younger Pakistani adults, we selected these cancers to study their etiology and respective response on mitochondria under stress conditions.
We have induced the expression of these proteases in (CRC) through heat mediated stress and tunicamycin (drug) induced ER stress and then monitored the transcription level of these proteases through Real Time PCR. The protein level of these proteases is observed through western blotting. Reactive oxygen levels were also observed after induction of these proteases. Moreover, the effect of these proteases on mitochondrial gene expression was studied and interesting results were obtained. Overexpression of these proteases correlates with an increase in transcription of the mitochondrial genome and therefore, we can regulate the mitochondrial genetic machinery by targeting these proteases.
Mitochondria has important roles in initiating tumor malignancies. On one side it’s the central energy-generating organelle and aid in important cellular processes, it’s also involved in the generation of Reactive Oxygen species and mediators of intrinsic apoptosis. In tumorigenesis, cancer cells acquire a selective growth advantage through a diminished capacity to undergo programmed cell death under the growth-restrictive condition, aberrant oncogene activation or genetic injuries. Understanding the regulation of mitochondrial genome and role of mitochondrial proteases in regulating its expression thus plays an important role in studying the organelle mechanism in tumor cells.