Our group challenges important clinical obstacles in cancer treatment and also presents new knowledge in cancer and insulin signaling biology. Our findings and approaches are novel and if our hypothesis proves to be right we will be able to introduce new targeted treatment strategies to reduce cisplatin resistance in solid cancers.
The target proteins, ASNA1 and GRP94 affect both insulin secretion and cisplatin resistance. Our studies will help to better understand how to reduce cisplatin resistance without reducing insulin secretion as well as increase our knowledge of ASNA1 and GRP94 roles in insulin/IGF signaling (IIS) and insulin secretion.
We have identified a novel target, ASNA1, to increase sensitivity to platinum-based drugs, which can be of major clinical importance. In our Cell paper we showed that ASNA1 is necessary for growth control and insulin secretion. Also, ASNA1 depletion cause increased sensitivity to the platinum drug cisplatin and we generated site directed mutations in ASNA-1 which cause cisplatin sensitivity while insulin secretion was intact.
While other studies biochemically and in vitro have shown that ASNA1 is necessary for post-translational insertion of Tail anchored (TA) proteins into the endoplasmic reticulum (ER) we are the first group to show this in vivo and more important; we have strong indications that ASNA1 has other key functions and that the insulin secretion function of ASNA1 is independent of its role in TA protein handling.
We apply an unconventional, innovative and novel approach to perform translational biology studies in cancer with the C. elegans model system. In vivo studies in C. elegans are comparatively time and cost efficient. Confirmatory experiments are then performed in human cancer and insulinoma cell lines. As one of the larger departments in Sweden for cancer surgery we can utilise large patients cohorts and cancer tissue biobanks to validate our hypothesis.
Current group members
Peter Naredi, MD, Professor
Gautam Kao, PhD, Researcher
Johan Bourghardt Fagman, Researcher
Dania Awata, Associate Researcher
Dorota Raj, PhD student
Agnieszka Podraza-Farhanieh, PhD student
- Future cancer research priorities in the USA: a Lancet Oncology Commission.
Jaffee EM., … Naredi P., et al. Lancet Oncol. 11:e653-e706, 2017.
- Asna1/TRC40 controls beta cell function and ER homeostasis by ensuring retrograde transport.
Norlin, S., Parekh, V., Naredi, P., Edlund, H. Diabetes 65 (1):110-119, 2016.
- The future of trials in surgical oncology.
Naredi, P., La Quaglia, M. Nature Reviews Clinical Oncology, 12:425-31, 2015.
- Delivering affordable cancer care in high income countries.
Sullivan, R., Peppercorn, J., Sikora, K., Naredi, P., et al. Lancet Oncol 12(10):933-80, 2011.
- Cisplatin binds human copper chaperone Atox1 and promotes unfolding in vitro.
Palm, M., Weise, C., Lundin, C., Wingsle, G., Nygren, Y., Björn, E., Naredi, P., Wolf-Watz, M., Wittung-Stafshede, P. Proc Natl Acad Sci USA 108(17):6951-6, 2011.
- ASNA-1 activity modulates sensitivity to cisplatin.
Hemmingsson, O., Kao, G., Still, M., Naredi, P. Cancer Res 70(24):10321-8, 2010.
- ASNA-1 positively regulates insulin secretion in C. elegans and mammalian cells.
Kao, G., Nordenson, C., Still, M., Rönnlund, A., Tuck, S., Naredi, P. Cell 128:577-87, 2007.
- Results from a randomized phase III study comparing combined treatment with histamine dihydrochloride plus interleukin-2 versus interleukin-2 alone in patients with metastatic melanoma.
Agarwala, S., Glaspy, J., O’Day, S., Mitchell, M., Gutheil, J., Whitman, E., Gonzalez, R., Hersh, E., Feun, L., Belt, R., Meyskens, F., Hellstrand, K., Wood, D., Kirkwood, J.M., Gehlsen, K.R., Naredi, P. J Clin Oncol 20:125-33, 2002.
- Histamine, cimetedin and colorectal cancer.
Hellstrand, K., Brune, M., Mellqvist, U-H. Naredi, P. Nature Med 2:364-5, 1996.
- Cross-resistance between cisplatin, antimony potassium tartrate, and arsenite in human tumor cells.
Naredi, P., Heath, D. D., Enns, R. E., Howell, S.B. J Clin Invest 95:1193-8, 1995.
More group Peter Naredi publications on PubMed