Pem renders tumor cells resistant to apoptotic cell death induced by a CD8+ T cell-mediated immune response or anticancer drug treatment.
Pem, a member of homeobox genes, is an oncofetal gene which is preferentially expressed in reproductive tissues and in multiple tumor cell lines. However, the function of Pem in tumor cell lines has not been elucidated. Herein we report that the ectopic expression of Pem in TC-1, a human papillomavirus type 16 (HPV-16) E7-expressing surrogate cervical tumor cell line, demonstrated a significant increase in extracellular signal-regulated kinase (ERK) activity and multiple resistance to various apoptotic pressures from an E7-specific CD8(+) T cell-mediated immune response and anticancer drug treatment. The observed resistance to apoptotic death of the Pem-over-expressing TC-1 tumor cells (TC-1/Pem) was associated with the down-regulation of a pro-apoptotic molecule, such as BIM, and up-regulation of an anti-apoptotic molecule, such as Bcl-2 protein, which mediated ERK activation. We also observed that the intratumoral injection of an ERK inhibitor enhanced the therapeutic efficacy of E7-specific CD8(+) T cell adoptive transfer or anticancer drug treatment against the resistant TC-1/Pem tumor. This is the first evidence demonstrating an association between Pem and a signaling pathway, namely the ERK-mediated survival signal transduction pathway. Thus, our data indicate that activation of the ERK pathway represents a new mechanism of Pem-mediated multiple resistances and the present research will contribute to the development of a novel strategy in cancer therapy against Pem-over-expressing tumor cells.
Kim
Seok-Ho
SH
Laboratory of Infection and Immunology, Graduate School of Medicine, Korea University, Seoul, South Korea.
Kim
Keon Woo
KW
Kim
Jin Hee
JH
Noh
Kyung Hee
KH
Bae
Hyun Cheol
HC
Lee
Tae-Hoon
TH
Kim
Tae Woo
TW
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D019008:Drug Resistance, Neoplasm; D005260:Female; D005801:Genes, Homeobox; D018398:Homeodomain Proteins / Q000235:genetics*; D007165:Immunosuppression Therapy; D008175:Lung Neoplasms / Q000235:genetics*; D051379:Mice; D014157:Transcription Factors / Q000235:genetics*
D000970:Antineoplastic Agents; D018398:Homeodomain Proteins; D014157:Transcription Factors; C498048:Rhox5 protein, mouse