Plastic Surgery Research Council
Members Only  |  Contact  |  PSRC on Facebook
PSRC 60th Annual Meeting
Program and Abstracts

Back to 2015 Annual Meeting Program


Attenuation of Autophagy via local SGK-1 Inhibition in SCC of the Head and Neck may sensitize to Cisplatin Therapy
Henrik O. Berdel, MD1, Jun Liu, BS2, Mahmood Mozaffari, PhD2, Jack C. Yu, MD2, Babak Baban, PhD2.
1Palmetto Health / University of South Carolina, Columbia, SC, USA, 2Georgia Regents University, Augusta, GA, USA.

PURPOSE:
We have recently found that the Serum glucocorticoid-regulated kinase-1 (SGK-1) significantly decreases growth of Head and Neck squamous cell carcinoma (HNSCC) when competitively inhibited by local injection, particularly in combination with systemic cisplatin. However, caspase dependant cell death alone did not explain why combination therapy was superior. Moreover, growth was not inhibited completely, and some animals exhibited features of resistance. Autophagy has been discussed as possible mechanism of resistance to chemotherapeutic agents including cisplatin in various cancers, and was identified as a potentially promising additional target for cancer treatment. In this study we tested for autophagic activity by detection of LC3 antibody after local SGK-1 inhibition, systemic cisplatin, and a combination of both.
METHODS:
Human head and neck tumors (HTB41/43) were established subcutaneously in athymic mice. Mice were subjected to treatment with local vehicle injection (control-group 1, n=5), local SGK-1 Inhibitor injection (group 2; n=6), systemic cisplatin (group 3; n=6), and a combination of local SGK-1 Inhibitor injection and systemic cisplatin (group 4; n=6). Tumor cells were subsequently submitted to immunohistochemistry (figure 1), and quantitative analysis of LC3 antibody staining. Groups were compared using one-way ANOVA with Newman-Keuls Multiple Comparison Test (p < 0.05).
RESULTS:
LC3 expression was 1063.67 +/- 513.38, 10264.00 +/- 7105.53, 28692.25 +/- 14287.41, 17977.00 +/- 11147.80 % total cells (mean +/- SD) for groups 1 to 4 (figure 2). SGK-1 inhibition did not lead to significantly increased LC3 expression, whereas Cisplatin showed a statistically significant increase (p < 0.024). Interestingly, LC3 expression was reduced when local SGK-1 Inhibitor was added to cisplatin, and not significantly different compared to controls. However, direct comparison of cisplatin and combination therapy did not reveal a statistically significant difference (p = 0.284). Nevertheless, power analysis between these groups revealed under-powering (48.50%).
CONCLUSION:
Autophagy has been described as a survival mechanism to overcome stresses imposed during cancer progression, as well as those caused by radiation or chemotherapy. We found that systemic cisplatin lead to higher levels of autophagic activity compared to controls, demonstrating a thrive of cancer cells to survive under genotoxic conditions. Interestingly, with combination of both systemic cisplatin and local SGK-1 inhibition there was less evidence of autophagy than with cisplatin alone. We believe that autophagic pathways may be attenuated by SGK-1 inhibition in these circumstances, and thereby render cancer cells more susceptible to cisplatin. Further studies are necessary to clarify the specific role of SGK-1 inhibition in autophagy, and its interaction with cisplatin. Finally, autophagy may be a promising additional target during cisplatin therapy of HNSCC.
Figure 1:

Figure 2:


Back to 2015 Annual Meeting Program