Localized traumatic stress, including oxidative and thermal stress inflicted by some types of cancer therapy, provokes in targeted cells a homeostatic, evolutionarily well-preserved canonic protection mechanism operated by signaling networks centered on the integrated stress response (ISR) and associated unfolded protein response (UPR). The stressor, misfolded protein accumulated in elevated numbers in endoplasmic reticulum (ER), is detected by sensor kinases that prompt upon their activation the engagement of eukaryotic translation initiation factor eIF2. This factor is responsible for the downregulation of overall rate of translation for protein synthesis and the induction of stress response genes. In case when proteostasis cannot be re-established due to severity of adverse effects, the cell survival-promoting adaptive phase of stress response turns into lethal phase endorsing cell death through apoptosis and lethal autophagy. Our research has shown that de novo biosynthesis of sphingolipids (localized in the ER) becomes upregulated in cellular stress response and that its key members, ceramide, dihydroceramide, and sphingosine-1-phosphate (S1P), play a critical role in the fate of cells sustaining adverse stress effects. It will be shown that the ceramide synthase inhibitor LCL521 (that causes an increase in ceramide levels with concomitant decrease in S1P) strongly reduces survival of tumor cells treated by oxidative stress-inducing photodynamic therapy (PDT). A series of selective inhibitors of various elements of cellular stress signaling pathways were employed to uncover vital steps affected by modulating the balance of key bioactive sphingolipids. The findings identify novel therapeutic targets in cellular stress-inducing cancer treatments.Biography:
Mladen Korbelik is a Distinguished Scientist at the Department of Integrative Oncology at the British Columbia Cancer Agency in Vancouver (British Columbia, Canada). He is also a Clinical Professor at the Department of Pathology and Laboratory Medicine, University of British Columbia. He holds a Master and PhD degrees in Biology and Bachelor Science degree in Chemistry, all from the University of Zagreb (Croatia). Prof. Korbelik has published close to 250 scientific papers including scientific book chapters and made over 200 presentations at scientific conferences during the past 45 years. In turn, he served as a manuscript reviewer for many scientific journals and on the editorial board of several journals. He had contributed to the work of scientific conferences on many occasions as a session organizer, chair, keynote or invited speaker. He has served as a panel member and reviewer for various scientific granting agencies in Canada, USA and elsewhere. His leadership activities in the international scientific community include the membership in the Directorship Board for International Photodynamic Association and serving as a Board Member and Founding Fellow of PanAmerican Photodynamic Association. He has served as a panel member and reviewer for various scientific granting agencies in Canada, USA and elsewhere. Among the achievements in scientific research, best known are his contributions to the understanding of cellular, immune and other systemic responses to oxidative stress-inducing cancer therapies such as photodynamic therapy.