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P73 regulates cisplatin...

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  • 작성일 2020-12-14
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Benjamin K. Tsang교수 연구실 논문 소개

제목 : P73 regulates cisplatin-induced apoptosis in ovarian cancer cells via a calcium/calpain dependent mechanism.
저자 : Al-Bahlani S, Fraser M, Wong AY, Sayan BS,
Bergeron R, Melino G, Tsang BK.
게재지 : Oncogene. 2011 Apr 25. [Epub ahead of print]
Impact factor : 7.414 (Top 10% journal)

본 논문은 인간의 난소암에서 cisplatin (CDDP)에 유도된 세포사
멸과정중 p73α 기능조절을 위한 칼슘에 매개된 calpain의 새로운
기능을 규명했다.
P73은 몇종류의 암세포주에서 세포사멸을 유도하는것으로 알려진
중요한 인자이지만, 난소암에 대한 화학적요법에서는 알려진바가 거
의 없다. 따라서 Tsang교수 연구팀은 본 연구를 통하여 다양한 난
소암 세포주를 이용하여 CDDP에 유도된 p73 감소조절은 calpain
에 의존한 세포신호전달임을 밝혔다. 연구진은 이밖에도 p73 와
calpain 간의 세포내 co-localization 과 상호작용을 밝혔으며, 세
포내 칼슘의 농도가 미치는 영향까지 측정했다.
결과적으로, p73 과 칼슘에 매개된 calpain 의 세포내 신호전달은
난소암세포주에서 CDDP에 유도된 세포사멸과 깊은 관련이 있으며,
더나아가 CDDP 저항성에 관련된 병리·생리학적인 측면에도 관여하
리라 예측했다. 이러한 화학적치료제에 대한 세포학적, 분자생물학
적 메커니즘의 규명은 난소암 치료를 위한 화학적요법에 대한 새로
운 방향을 제시할것이다.

The results of this study from Dr. Tsang’s lab demonstrated that a
novel role of Ca2+-mediated, calpain activation in regulating p73α
function in CDDP-induced apoptosis in human ovarian cancer. P73
is important in drug-induced apoptosis in some cancer cells, yet its
role in the regulation of chemosensitivity in ovarian cancer
(OVCA) is poorly understood. Furthermore, if and how the
deregulation of p73-mediated apoptosis confers resistance to
cisplatin (CDDP) treatment is unclear. The authors demonstrated
that TAp73α over-expression enhanced CDDP-induced PARP
cleavage and apoptosis in both chemosensitive (OV2008 and
A2780s) and their resistant counterparts (C13* and A2780cp) and
another chemoresistant OVCA cells (Hey); in contrast, the effect of
ΔNp73α over-expression was variable. P73α downregulation
attenuated CDDP-induced PUMA and NOXA upregulation and
apoptosis in OV2008 cells. CDDP decreased p73α steady-state
protein levels in OV2008, but not in C13*, although the mRNA
expression was identical. CDDP-induced p73α downregulation was
mediated by a calpain-dependent pathway. CDDP induced calpain
activation and enhanced its cytoplasmic interaction and
co-localization with p73α in OV2008, but not C13* cells. CDDP
increased the intracellular calcium concentration ([Ca2+]i) in
OV2008 but not C13* whereas cyclopiazonic acid (CPA), a Ca2+-
ATPase inhibitor, caused this response and calpain activation, p73α
processing and apoptosis in both cell types. CDDP-induced [Ca2+]i
increase in OV2008 cells was not effected by the elimination of
extracellular Ca2+, but this was attenuated by the depletion of
internal Ca2+ store, indicating that mobilization of intracellular
Ca2+ stores was potentially involved. These findings demonstrate
that p73α and its regulation by the Ca2+-mediated calpain pathway
are involved in CDDP-induced apoptosis in OVCA cells and that
dysregulation of Ca2+/calpain/p73 signaling may in part be the
pathophysiology of CDDP resistance. Understanding the cellular
and molecular mechanisms of chemoresistance will direct the
development of effective strategies for the treatment of
chemoresistant OVCA.