Heat shock phenocopies E1B-55K late functions and selectively sensitizes refractory tumor cells to ONYX-015 oncolytic viral therapy

Cancer Cell. 8(1):61-74. (2005)

Speaker：王瑋祥                             Time：2005/10/12, 13:10~14:00

Commentator：翁舷誌老師                    Place：Room 601

Abstract：

  ONYX-015 is an E1B-55K mutant adenovirus that undergoes selective lytic replication in tumor cells in which the p53 pathway is inactive. Except for degradation of p53, E1B-55K also has late functions that include the shutdown of host protein synthesis and the preferential export and translation of late viral mRNAs, both necessary events for a productive viral infection. Recently, it has been shown that the loss of E1B-55K-mediated late functions, rather than p53 inactivation, is the major determinant of ONYX-015’s oncolytic selectivity¹. In this study, the authors first showed that tumor cell differences in providing the host protein shutoff and RNA export functions of E1B-55K correlate with ONYX-015 permissivity/resistance. Because 100K inhibits the translation of many cellular mRNAs but promotes the translation of late viral RNAs, they demonstrated that 100K expression is at least one of the critical rate-limiting factors for ONYX-015 replication and late protein production in resistant tumor cell lines. Furthermore, the cellular response to heat shock resembles the late stages of adenovirus infection in many ways. Heat shock actually rescues host protein shutoff and late viral protein expression in ONYX-015-infected U2OS cells. Moreover, not only heat shock, but also its pharmacological inducers, such as benzoquinoid ansamycins, which include herbimycin A, radicicol, geldanamycin, and 17-AAG, could rescue ONYX-015 replication in resistant tumor cells. Notably, heat shock did not rescue 100K expression in ONYX-015-infected primary quiescent small airway epithelial cells (SAECs) or other normal cells, which was not due to heat shock-induced premature apoptosis, cell cycle arrest, or defective p53 degradation in adenovirus-infected primary cells. Taken together, this study indicates that induction of a heat shock response by pharmacological agents that could potentially be administered systemically or local hyperthermia, could greatly augment and broaden ONYX-015’s clinical utility as a cancer therapy.

References：

1.      O'Shea CC, et al. Late viral RNA export, rather than p53 inactivation, determines ONYX-015 tumor selectivity. Cancer Cell. 6, 611-23, 2004.

2.      O'Shea CC, et al. Heat shock phenocopies E1B-55K late functions and selectively sensitizes refractory tumor cells to ONYX-015 oncolytic viral therapy. Cancer Cell. 8, 61-74, 2005.