Elimination of hepatic metastases of colon cancer cells via p53-independent cross-talk between irinotecan and Apo2 ligand/TRAIL

Rajani Ravi, Ajay J. Jain, Richard D. Schulick, Vui Pham, Traci S. Prouser, Heather Allen, Elizabeth Garrett Mayer, Hua Yu, Andrew Mark Pardoll, Avi Ashkenazi, Atul Bedi

Research output: Contribution to journalArticle

Abstract

The majority of colorectal cancers have lost/inactivated the p53 tumor suppressor gene. Using isogenic human colon cancer cells that differ only in their p53 status, we demonstrate that loss of p53 renders tumor cells relatively resistant to the topoisomerase I inhibitor, irinotecan. Whereas irinotecan-induced up-regulation of the proapoptotic proteins PUMA and Noxa requires p53, we find that irinotecan inhibits Janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 and 5 (STAT3/5) signaling in both p53-proficient and p53-deficient tumor cells. We show that irinotecan inhibits JAK2-STAT3/5-dependent expression of survival proteins (Bcl-xL and XIAP) and cooperates with Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) to facilitate p53-independent apoptosis of colon cancer cells. Whereas xenografts of p53-deficient colon cancer cells are relatively resistant to irinotecan compared with their p53-proficient counterparts, combined treatment with irinotecan and Apo2L/TRAIL eliminates hepatic metastases of both p53-proficient and p53-deficient cancer cells in vivo and significantly improves the survival of animals relative to treatment with either agent alone. Although the synergy between chemotherapy and Apo2L/TRAIL has been ascribed to p53, our data demonstrate that irinotecan enhances Apo2L/TRAIL-induced apoptosis of tumor cells via a distinct p53-independent mechanism involving inhibition of JAK2-STAT3/5 signaling. These findings identify a novel p53-independent channel of cross-talk between topoisomerase I inhibitors and Apo2L/TRAIL and suggest that the addition of Apo2L/TRAIL can improve the therapeutic index of irinotecan against both p53-proficient and p53-deficient colorectal cancers, including those that have metastasized to the liver.

Original languageEnglish (US)
Pages (from-to)9105-9114
Number of pages10
JournalCancer Research
Volume64
Issue number24
DOIs
StatePublished - Dec 15 2004

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irinotecan
Colonic Neoplasms
Neoplasm Metastasis
Ligands
Apoptosis
Tumor Necrosis Factor-alpha
STAT5 Transcription Factor
Janus Kinase 2
STAT3 Transcription Factor
Topoisomerase I Inhibitors
Hepatobiliary Elimination
Colorectal Neoplasms
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Elimination of hepatic metastases of colon cancer cells via p53-independent cross-talk between irinotecan and Apo2 ligand/TRAIL. / Ravi, Rajani; Jain, Ajay J.; Schulick, Richard D.; Pham, Vui; Prouser, Traci S.; Allen, Heather; Mayer, Elizabeth Garrett; Yu, Hua; Pardoll, Andrew Mark; Ashkenazi, Avi; Bedi, Atul.

In: Cancer Research, Vol. 64, No. 24, 15.12.2004, p. 9105-9114.

Research output: Contribution to journalArticle

Ravi, Rajani ; Jain, Ajay J. ; Schulick, Richard D. ; Pham, Vui ; Prouser, Traci S. ; Allen, Heather ; Mayer, Elizabeth Garrett ; Yu, Hua ; Pardoll, Andrew Mark ; Ashkenazi, Avi ; Bedi, Atul. / Elimination of hepatic metastases of colon cancer cells via p53-independent cross-talk between irinotecan and Apo2 ligand/TRAIL. In: Cancer Research. 2004 ; Vol. 64, No. 24. pp. 9105-9114.
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abstract = "The majority of colorectal cancers have lost/inactivated the p53 tumor suppressor gene. Using isogenic human colon cancer cells that differ only in their p53 status, we demonstrate that loss of p53 renders tumor cells relatively resistant to the topoisomerase I inhibitor, irinotecan. Whereas irinotecan-induced up-regulation of the proapoptotic proteins PUMA and Noxa requires p53, we find that irinotecan inhibits Janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 and 5 (STAT3/5) signaling in both p53-proficient and p53-deficient tumor cells. We show that irinotecan inhibits JAK2-STAT3/5-dependent expression of survival proteins (Bcl-xL and XIAP) and cooperates with Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) to facilitate p53-independent apoptosis of colon cancer cells. Whereas xenografts of p53-deficient colon cancer cells are relatively resistant to irinotecan compared with their p53-proficient counterparts, combined treatment with irinotecan and Apo2L/TRAIL eliminates hepatic metastases of both p53-proficient and p53-deficient cancer cells in vivo and significantly improves the survival of animals relative to treatment with either agent alone. Although the synergy between chemotherapy and Apo2L/TRAIL has been ascribed to p53, our data demonstrate that irinotecan enhances Apo2L/TRAIL-induced apoptosis of tumor cells via a distinct p53-independent mechanism involving inhibition of JAK2-STAT3/5 signaling. These findings identify a novel p53-independent channel of cross-talk between topoisomerase I inhibitors and Apo2L/TRAIL and suggest that the addition of Apo2L/TRAIL can improve the therapeutic index of irinotecan against both p53-proficient and p53-deficient colorectal cancers, including those that have metastasized to the liver.",
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AU - Schulick, Richard D.

AU - Pham, Vui

AU - Prouser, Traci S.

AU - Allen, Heather

AU - Mayer, Elizabeth Garrett

AU - Yu, Hua

AU - Pardoll, Andrew Mark

AU - Ashkenazi, Avi

AU - Bedi, Atul

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