Blockage of Stat3 enhances the sensitivity of NSCLC cells to PI3K/mTOR inhibition.
The PI3K/Akt/mTOR axis in lung cancer is frequently activated and implicated in tumorigenesis. Specific targeting of this pathway is therefore an attractive therapeutic approach for lung cancer. However, non-small cell lung cancer cells are resistant to BEZ235, a dual inhibitor of PI3K and mTOR. Interestingly, blockage of Stat3 with a selective inhibitor, S3I-201, or siRNA dramatically sensitized the BEZ235-induced cell death, as evident from increased PARP cleavage. Furthermore, inhibition of Stat3 led to enhancement of cell death induced by LY294002, a PI3K inhibitor. Treatment of cells with a combination of BEZ235 and S3I-201 significantly induced the proapoptotic transcription factor, CHOP, and its targets, Bim and DR4. Knockdown of CHOP or Bim suppressed cell death stimulated by the combination treatment, implicating the involvement of these BEZ235/S3I-201-induced factors in pronounced cell death. Moreover, the BEZ235/S3I-201 combination enhanced TRAIL-induced cell death. Our results collectively suggest that blockage of Stat3 presents an effective strategy to overcome resistance to PI3K/Akt/mTOR inhibition.
KIRAMS Radiation Blood Specimen Biobank, Korea Institute of Radiological & Medical Sciences, 215-4 Gongneung-dong, Nowon-gu, Seoul 139-709, Republic of Korea.
Hyeon-Ok
HO
Jin
Department of Radiation Oncology, College of Medicine, Yonsei University, 250 Seongsan-no, Seodaemun-gu, Seoul 120-752, Republic of Korea.
Yun-Han
YH
Lee
KIRAMS Radiation Blood Specimen Biobank, Korea Institute of Radiological & Medical Sciences, 215-4 Gongneung-dong, Nowon-gu, Seoul 139-709, Republic of Korea.
Jin-Ah
JA
Park
KIRAMS Radiation Blood Specimen Biobank, Korea Institute of Radiological & Medical Sciences, 215-4 Gongneung-dong, Nowon-gu, Seoul 139-709, Republic of Korea.
Jin-Hee
JH
Kim
Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, 215-4 Gongneung-dong, Nowon-gu, Seoul 139-706, Republic of Korea.
Sung-Eun
SE
Hong
Department of Surgery, Korea Cancer Center Hospital, Korea Institute of Radiological & Medical Sciences, 215-4 Gongneung-dong, Nowon-gu, Seoul 139-706, Republic of Korea.
Hyun-Ah
HA
Kim
Department of Surgery, Korea Cancer Center Hospital, Korea Institute of Radiological & Medical Sciences, 215-4 Gongneung-dong, Nowon-gu, Seoul 139-706, Republic of Korea.
Eun-Kyu
EK
Kim
Department of Surgery, Korea Cancer Center Hospital, Korea Institute of Radiological & Medical Sciences, 215-4 Gongneung-dong, Nowon-gu, Seoul 139-706, Republic of Korea.
Woo Chul
WC
Noh
Department of Pharmacology, Seoul National University College of Medicine, 103 Daehangno, Jongno-gu, Seoul 110-799, Republic of Korea.
Byung-Hak
BH
Kim
Department of Pharmacology, Seoul National University College of Medicine, 103 Daehangno, Jongno-gu, Seoul 110-799, Republic of Korea.
Sang-Kyu
SK
Ye
Department of Laboratory Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, 215-4 Gongneung-dong, Nowon-gu, Seoul 139-709, Republic of Korea.
Yoon Hwan
YH
Chang
Department of Laboratory Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, 215-4 Gongneung-dong, Nowon-gu, Seoul 139-709, Republic of Korea.
Seok-Il
SI
Hong
Department of Laboratory Medicine, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, 215-4 Gongneung-dong, Nowon-gu, Seoul 139-709, Republic of Korea.
Young-Joon
YJ
Hong
Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, 215-4 Gongneung-dong, Nowon-gu, Seoul 139-706, Republic of Korea. Electronic address: parkic@kirams.re.kr.
In-Chul
IC
Park
KIRAMS Radiation Blood Specimen Biobank, Korea Institute of Radiological & Medical Sciences, 215-4 Gongneung-dong, Nowon-gu, Seoul 139-709, Republic of Korea. Electronic address: jklee@kirams.re.kr.
Jin Kyung
JK
Lee
D000636:Aminosalicylic Acids / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D001557:Benzenesulfonates / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000636:Aminosalicylic Acids; D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D007093:Imidazoles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; D058570:TOR Serine-Threonine Kinases; C520337:NSC 74859; C546842:MTOR protein, human; C531198:dactolisib
Akt; Bim; CHOP; PI3K; Stat3; mTOR