PIM1 kinase inhibitors induce radiosensitization in non-small cell lung cancer cells.
Radiotherapy plays a critical role in the treatment of non-small cell lung cancer (NSCLC). However, radioresistance is a major barrier against increasing the efficiency of radiotherapy for NSCLC. To understand the mechanisms underlying NSCLC radioresistance, we previously focused on the potential involvement of PIM1, PRAS40, FOXO3a, 14-3-3, and protein phosphatases. Among these proteins, PIM1 functioned as an oncogene and was found to act as a crucial mediator in radioresistant NSCLC cells. Therefore, we investigated the use of PIM1-specific inhibitors as novel therapeutic drugs to regulate radiosensitivity in NSCLC. After structure-based drug selection, SGI-1776, ETP-45299, and tryptanthrin were selected as candidates of PIM1 inhibitors that act as radiosensitizers. With irradiation, these drugs inhibited only PIM1 kinase activity without affecting PIM1 mRNA/protein levels or cellular localization. When PIM1 kinase activity was suppressed by these inhibitors, PRAS40 was not phosphorylated. Consequently, unphosphorylated PRAS40 did not form trimeric complexes with 14-3-3 and FOXO3a, leading to increased nuclear localization of FOXO3a. Nuclear FOXO3a promoted the expression of pro-apoptotic proteins such as Bim and FasL, resulting in a radiosensitizing effect on radioresistant NSCLC cells. Moreover, an in vivo xenograft mouse model confirmed this radiosensitizing effect induced by PIM1 inhibitors. In these model systems, tumor volume was significantly reduced by a combinational treatment with irradiation and PIM1 inhibitors compared to irradiation alone. Taken together, our findings provided evidence that PIM1-specific inhibitors, SGI-1776, ETP-45299, and tryptanthrin, can act as novel radiosensitizers to enhance the efficacy of radiotherapy by inhibiting irradiation-induced signaling pathway associated with radioresistance.
Department of Biological Sciences, Pusan National University, Busandaehak-ro 63, Geumjeong-gu, Busan, 609-735, South Korea.
Wanyeon
W
Kim
HyeSook
H
Youn
TaeWoo
T
Kwon
JiHoon
J
Kang
EunGi
E
Kim
Beomseok
B
Son
Hee Jung
HJ
Yang
Youngmi
Y
Jung
BuHyun
B
Youn
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000473:pathology / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000473:pathology / Q000532:radiotherapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors*; D011838:Radiation-Sensitizing Agents / Q000737:chemistry / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D011838:Radiation-Sensitizing Agents; C496634:PIM1 protein, human; D051573:Proto-Oncogene Proteins c-pim-1